Clinical Edge Journal Scan

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dupilumab is a subcutaneous injection therapy that inhibits the interleukin 4 receptor alpha subunit. It has been approved in the United States for the treatment of adults with moderate-to-severe AD since 2017 and has since been approved for children and adolescents older than 6 years. Many real-world studies of the effectiveness of dupilumab have been published over the past few years. Kojanova and colleagues reported findings from a retrospective, multicenter study of 360 adults with severe AD who received dupilumab. They found that a high proportion of patients achieved a 75% improvement in the Eczema Area and Severity Index (EASI-75) at week 16 (66.6%), 1 year (89.5%), and 2 years (95.8%). Drug persistence rates were very high (> 90%) throughout the 2 years of therapy, suggesting that dupilumab was effective and well-tolerated.

Dupilumab was previously found to be associated with increased conjunctivitis in clinical trials and real-world studies. Schneeweiss and colleagues conducted a population-based longitudinal study of 5,004,117 patients with AD who newly initiated dupilumab, methotrexate, mycophenolate, and cyclosporine. They found that the risk of developing conjunctivitis diagnosed in clinical practice within 6 months of treatment initiation was approximately double with dupilumab compared with methotrexate, mycophenolate, or cyclosporine. Interestingly, comorbid asthma was found to be a risk factor for conjunctivitis in dupilumab initiators. This study provides insight into how commonly clinically significant conjunctivitis occurs with dupilumab treatment. Of note, the study results may underestimate the incidence of conjunctivitis because milder cases may go undetected.

Upadacitinib is an oral selective Janus kinase (JAK) 1 inhibitor that was approved in the United States in 2022 for the treatment of moderate-to-severe AD. Simpson and colleagues reported on the long-term efficacy and safety of oral upadacitinib from the phase 3 double-blind, randomized controlled trials Measure Up 1 and Measure Up 2 in adolescents and adults with moderate-to-severe atopic dermatitis ho had an inadequate response to topical therapy. The initial phase of the Measure Up 1 and Measure Up 2 studies was 16 weeks in duration, with a placebo control group. At week 16, patients who received 15 or 30 mg upadacitinib in the initial 16 weeks of the study continued to receive that dose. Patients who received placebo in the initial 16 weeks were randomly assigned to receive oral 15 mg or 30 mg upadacitinib daily. So, in the long run, all patients received upadacitinib in the second phase of the study but were blinded to the dose they were receiving. The results from the first 16 weeks of treatment were previously published. Simpson and colleagues reported on the results up to week 52 from the second phase of the study. They showed that at week 52, 82.0% and 79.1% of patients in Measure Up 1 and Measure Up 2 achieved a 75% improvement in EASI-75 when continuing on 15 mg upadacitinib and 84.9% and 84.3% in patients continuing 30 mg upadacitinib, respectively. More than 80% of patients who switched from placebo to upadacitinib at week 16 achieved EASI-75 at week 52. No safety signals were observed in this phase of the study that were not previously observed in other studies of upadacitinib for atopic dermatitis and other indications (rheumatoid arthritis and psoriatic arthritis). These results indicate that upadacitinib has durable efficacy with long-term treatment in moderate-to-severe AD. These studies are ongoing, and I look forward to future results reporting for even longer-term treatment.

It is an exciting time in dermatology with the arrival of multiple novel therapies for atopic dermatitis. The field has already benefited so much by the tremendous interest and research effort into understanding how to best manage this disease. With so many more treatments in the pipeline, perhaps the best is yet to come.

Dupilumab is a subcutaneous injection therapy that inhibits the interleukin 4 receptor alpha subunit. It has been approved in the United States for the treatment of adults with moderate-to-severe AD since 2017 and has since been approved for children and adolescents older than 6 years. Many real-world studies of the effectiveness of dupilumab have been published over the past few years. Kojanova and colleagues reported findings from a retrospective, multicenter study of 360 adults with severe AD who received dupilumab. They found that a high proportion of patients achieved a 75% improvement in the Eczema Area and Severity Index (EASI-75) at week 16 (66.6%), 1 year (89.5%), and 2 years (95.8%). Drug persistence rates were very high (> 90%) throughout the 2 years of therapy, suggesting that dupilumab was effective and well-tolerated.

Dupilumab was previously found to be associated with increased conjunctivitis in clinical trials and real-world studies. Schneeweiss and colleagues conducted a population-based longitudinal study of 5,004,117 patients with AD who newly initiated dupilumab, methotrexate, mycophenolate, and cyclosporine. They found that the risk of developing conjunctivitis diagnosed in clinical practice within 6 months of treatment initiation was approximately double with dupilumab compared with methotrexate, mycophenolate, or cyclosporine. Interestingly, comorbid asthma was found to be a risk factor for conjunctivitis in dupilumab initiators. This study provides insight into how commonly clinically significant conjunctivitis occurs with dupilumab treatment. Of note, the study results may underestimate the incidence of conjunctivitis because milder cases may go undetected.

Upadacitinib is an oral selective Janus kinase (JAK) 1 inhibitor that was approved in the United States in 2022 for the treatment of moderate-to-severe AD. Simpson and colleagues reported on the long-term efficacy and safety of oral upadacitinib from the phase 3 double-blind, randomized controlled trials Measure Up 1 and Measure Up 2 in adolescents and adults with moderate-to-severe atopic dermatitis ho had an inadequate response to topical therapy. The initial phase of the Measure Up 1 and Measure Up 2 studies was 16 weeks in duration, with a placebo control group. At week 16, patients who received 15 or 30 mg upadacitinib in the initial 16 weeks of the study continued to receive that dose. Patients who received placebo in the initial 16 weeks were randomly assigned to receive oral 15 mg or 30 mg upadacitinib daily. So, in the long run, all patients received upadacitinib in the second phase of the study but were blinded to the dose they were receiving. The results from the first 16 weeks of treatment were previously published. Simpson and colleagues reported on the results up to week 52 from the second phase of the study. They showed that at week 52, 82.0% and 79.1% of patients in Measure Up 1 and Measure Up 2 achieved a 75% improvement in EASI-75 when continuing on 15 mg upadacitinib and 84.9% and 84.3% in patients continuing 30 mg upadacitinib, respectively. More than 80% of patients who switched from placebo to upadacitinib at week 16 achieved EASI-75 at week 52. No safety signals were observed in this phase of the study that were not previously observed in other studies of upadacitinib for atopic dermatitis and other indications (rheumatoid arthritis and psoriatic arthritis). These results indicate that upadacitinib has durable efficacy with long-term treatment in moderate-to-severe AD. These studies are ongoing, and I look forward to future results reporting for even longer-term treatment.

It is an exciting time in dermatology with the arrival of multiple novel therapies for atopic dermatitis. The field has already benefited so much by the tremendous interest and research effort into understanding how to best manage this disease. With so many more treatments in the pipeline, perhaps the best is yet to come.

Dupilumab is a subcutaneous injection therapy that inhibits the interleukin 4 receptor alpha subunit. It has been approved in the United States for the treatment of adults with moderate-to-severe AD since 2017 and has since been approved for children and adolescents older than 6 years. Many real-world studies of the effectiveness of dupilumab have been published over the past few years. Kojanova and colleagues reported findings from a retrospective, multicenter study of 360 adults with severe AD who received dupilumab. They found that a high proportion of patients achieved a 75% improvement in the Eczema Area and Severity Index (EASI-75) at week 16 (66.6%), 1 year (89.5%), and 2 years (95.8%). Drug persistence rates were very high (> 90%) throughout the 2 years of therapy, suggesting that dupilumab was effective and well-tolerated.

Dupilumab was previously found to be associated with increased conjunctivitis in clinical trials and real-world studies. Schneeweiss and colleagues conducted a population-based longitudinal study of 5,004,117 patients with AD who newly initiated dupilumab, methotrexate, mycophenolate, and cyclosporine. They found that the risk of developing conjunctivitis diagnosed in clinical practice within 6 months of treatment initiation was approximately double with dupilumab compared with methotrexate, mycophenolate, or cyclosporine. Interestingly, comorbid asthma was found to be a risk factor for conjunctivitis in dupilumab initiators. This study provides insight into how commonly clinically significant conjunctivitis occurs with dupilumab treatment. Of note, the study results may underestimate the incidence of conjunctivitis because milder cases may go undetected.

Upadacitinib is an oral selective Janus kinase (JAK) 1 inhibitor that was approved in the United States in 2022 for the treatment of moderate-to-severe AD. Simpson and colleagues reported on the long-term efficacy and safety of oral upadacitinib from the phase 3 double-blind, randomized controlled trials Measure Up 1 and Measure Up 2 in adolescents and adults with moderate-to-severe atopic dermatitis ho had an inadequate response to topical therapy. The initial phase of the Measure Up 1 and Measure Up 2 studies was 16 weeks in duration, with a placebo control group. At week 16, patients who received 15 or 30 mg upadacitinib in the initial 16 weeks of the study continued to receive that dose. Patients who received placebo in the initial 16 weeks were randomly assigned to receive oral 15 mg or 30 mg upadacitinib daily. So, in the long run, all patients received upadacitinib in the second phase of the study but were blinded to the dose they were receiving. The results from the first 16 weeks of treatment were previously published. Simpson and colleagues reported on the results up to week 52 from the second phase of the study. They showed that at week 52, 82.0% and 79.1% of patients in Measure Up 1 and Measure Up 2 achieved a 75% improvement in EASI-75 when continuing on 15 mg upadacitinib and 84.9% and 84.3% in patients continuing 30 mg upadacitinib, respectively. More than 80% of patients who switched from placebo to upadacitinib at week 16 achieved EASI-75 at week 52. No safety signals were observed in this phase of the study that were not previously observed in other studies of upadacitinib for atopic dermatitis and other indications (rheumatoid arthritis and psoriatic arthritis). These results indicate that upadacitinib has durable efficacy with long-term treatment in moderate-to-severe AD. These studies are ongoing, and I look forward to future results reporting for even longer-term treatment.

It is an exciting time in dermatology with the arrival of multiple novel therapies for atopic dermatitis. The field has already benefited so much by the tremendous interest and research effort into understanding how to best manage this disease. With so many more treatments in the pipeline, perhaps the best is yet to come.

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

Treatment of psoriatic arthritis (PsA) was the focus of clinical research papers published this month. Despite the advances made in treating PsA with targeted therapies, in most parts of the world, conventional disease-modifying antirheumatic drugs (DMARDs) are the first line of treatment. Methotrexate (MTX) and leflunomide (LEF) are commonly used, but there are limited data on the effectiveness of combination therapy. To address this issue, Mulder and colleagues enrolled 78 patients with active PsA who have two or more swollen joints and randomly allocated them to either 25 mg oral MTX weekly after 4 weeks of 15 mg weekly plus 20 mg LEF daily (n = 39) or MTX plus placebo (monotherapy; n = 39). At week 16, PsA disease activity score was improved significantly in the MTX + LEF vs. MTX monotherapy group (3.1 vs. 3.7; P = .025). Incidence of mild adverse events, such as nausea/vomiting (44% vs. 28%) and altered bowel habits (26% vs. 8%), was higher with MTX + LEF vs. MTX + placebo. So although less well tolerated, MTX + LEF therapy was superior to MTX monotherapy at improving disease activity in patients with PsA.

Biologics targeting tumor necrosis factor (TNF), interleukin (IL) -12/23, -23, and -17A are efficacious for the management of PsA, but questions remain about comparative effectiveness. Gossec and colleagues reported the results from their prospective observational PsABio study that evaluated real-world treatment persistence and effectiveness at 1 year after initiation of first-line to third-line IL-12/23 inhibitor ustekinumab or a TNF inhibitor (TNFi). Their study followed 893 patients. After 1 year of treatment, ustekinumab and the TNFi showed similar persistence (hazard ratio [HR] for stopping/switching treatment 0.82; 95% CI 0.60-1.13) and a similar proportion of patients achieving (on the Disease Activity Index for PsA) clinical low disease activity (odds ratio [OR] 0.80; 95% CI 0.57-1.10) and remission (OR 0.73; 95% CI 0.49-1.07), along with similar safety profiles. Thus in real-world studies, TNFi and ustekinumab seem to have similar effectiveness and safety.

Drug persistence between patients with psoriasis alone vs. those with PsA is also of interest. In a real-life study including 62 patients with psoriasis and 90 patients with PsA who initiated treatment with secukinumab and were followed up for 24 months or until discontinuation, Ortolan and colleagues demonstrated that the retention rate of secukinumab was higher in psoriasis vs. PsA at 12 (85% vs. 68%) and 24 (61% vs. 57%) months, with the risk for secukinumab discontinuation being higher among patients with PsA in the overall cohort (HR 2.43; P = .035) and in patients with obesity in the PsA cohort (P = .021). Thus, the presence of PsA and obesity lower the secukinumab retention rate.

1. Despite the advent of many targeted therapies for PsA, there remain many unmet needs. Deucravacitinib is a novel oral selective inhibitor of tyrosine kinase 2 (TYK2) acting via binding to the TYK2 regulatory domain. In a phase 2 study including 203 patients with active PsA that was intolerant to at least one therapy who were randomly assigned to receive 6 mg deucravacitinib once daily, 12 mg deucravacitinib once daily, or placebo for 16 weeks, Mease and colleagues demonstrated that at week 16, American College of Rheumatology 20 (ACR20) response was significantly higher with 6 mg once-daily deucravacitinib (52.9%, adjusted OR [aOR] 2.4; P = .0134) and 12 mg (62.7%, aOR 3.6; P = .0004) vs. placebo (31.8%), with 12 mg deucravacitinib improving ACR20 response as early as at 8 weeks (P < .05). No serious adverse events were reported. Thus, TYK2 inhibition shows promise in the treatment of PsA and the results from phase 3 trials are awaited.

Treatment of psoriatic arthritis (PsA) was the focus of clinical research papers published this month. Despite the advances made in treating PsA with targeted therapies, in most parts of the world, conventional disease-modifying antirheumatic drugs (DMARDs) are the first line of treatment. Methotrexate (MTX) and leflunomide (LEF) are commonly used, but there are limited data on the effectiveness of combination therapy. To address this issue, Mulder and colleagues enrolled 78 patients with active PsA who have two or more swollen joints and randomly allocated them to either 25 mg oral MTX weekly after 4 weeks of 15 mg weekly plus 20 mg LEF daily (n = 39) or MTX plus placebo (monotherapy; n = 39). At week 16, PsA disease activity score was improved significantly in the MTX + LEF vs. MTX monotherapy group (3.1 vs. 3.7; P = .025). Incidence of mild adverse events, such as nausea/vomiting (44% vs. 28%) and altered bowel habits (26% vs. 8%), was higher with MTX + LEF vs. MTX + placebo. So although less well tolerated, MTX + LEF therapy was superior to MTX monotherapy at improving disease activity in patients with PsA.

Biologics targeting tumor necrosis factor (TNF), interleukin (IL) -12/23, -23, and -17A are efficacious for the management of PsA, but questions remain about comparative effectiveness. Gossec and colleagues reported the results from their prospective observational PsABio study that evaluated real-world treatment persistence and effectiveness at 1 year after initiation of first-line to third-line IL-12/23 inhibitor ustekinumab or a TNF inhibitor (TNFi). Their study followed 893 patients. After 1 year of treatment, ustekinumab and the TNFi showed similar persistence (hazard ratio [HR] for stopping/switching treatment 0.82; 95% CI 0.60-1.13) and a similar proportion of patients achieving (on the Disease Activity Index for PsA) clinical low disease activity (odds ratio [OR] 0.80; 95% CI 0.57-1.10) and remission (OR 0.73; 95% CI 0.49-1.07), along with similar safety profiles. Thus in real-world studies, TNFi and ustekinumab seem to have similar effectiveness and safety.

Drug persistence between patients with psoriasis alone vs. those with PsA is also of interest. In a real-life study including 62 patients with psoriasis and 90 patients with PsA who initiated treatment with secukinumab and were followed up for 24 months or until discontinuation, Ortolan and colleagues demonstrated that the retention rate of secukinumab was higher in psoriasis vs. PsA at 12 (85% vs. 68%) and 24 (61% vs. 57%) months, with the risk for secukinumab discontinuation being higher among patients with PsA in the overall cohort (HR 2.43; P = .035) and in patients with obesity in the PsA cohort (P = .021). Thus, the presence of PsA and obesity lower the secukinumab retention rate.

1. Despite the advent of many targeted therapies for PsA, there remain many unmet needs. Deucravacitinib is a novel oral selective inhibitor of tyrosine kinase 2 (TYK2) acting via binding to the TYK2 regulatory domain. In a phase 2 study including 203 patients with active PsA that was intolerant to at least one therapy who were randomly assigned to receive 6 mg deucravacitinib once daily, 12 mg deucravacitinib once daily, or placebo for 16 weeks, Mease and colleagues demonstrated that at week 16, American College of Rheumatology 20 (ACR20) response was significantly higher with 6 mg once-daily deucravacitinib (52.9%, adjusted OR [aOR] 2.4; P = .0134) and 12 mg (62.7%, aOR 3.6; P = .0004) vs. placebo (31.8%), with 12 mg deucravacitinib improving ACR20 response as early as at 8 weeks (P < .05). No serious adverse events were reported. Thus, TYK2 inhibition shows promise in the treatment of PsA and the results from phase 3 trials are awaited.

Treatment of psoriatic arthritis (PsA) was the focus of clinical research papers published this month. Despite the advances made in treating PsA with targeted therapies, in most parts of the world, conventional disease-modifying antirheumatic drugs (DMARDs) are the first line of treatment. Methotrexate (MTX) and leflunomide (LEF) are commonly used, but there are limited data on the effectiveness of combination therapy. To address this issue, Mulder and colleagues enrolled 78 patients with active PsA who have two or more swollen joints and randomly allocated them to either 25 mg oral MTX weekly after 4 weeks of 15 mg weekly plus 20 mg LEF daily (n = 39) or MTX plus placebo (monotherapy; n = 39). At week 16, PsA disease activity score was improved significantly in the MTX + LEF vs. MTX monotherapy group (3.1 vs. 3.7; P = .025). Incidence of mild adverse events, such as nausea/vomiting (44% vs. 28%) and altered bowel habits (26% vs. 8%), was higher with MTX + LEF vs. MTX + placebo. So although less well tolerated, MTX + LEF therapy was superior to MTX monotherapy at improving disease activity in patients with PsA.

Biologics targeting tumor necrosis factor (TNF), interleukin (IL) -12/23, -23, and -17A are efficacious for the management of PsA, but questions remain about comparative effectiveness. Gossec and colleagues reported the results from their prospective observational PsABio study that evaluated real-world treatment persistence and effectiveness at 1 year after initiation of first-line to third-line IL-12/23 inhibitor ustekinumab or a TNF inhibitor (TNFi). Their study followed 893 patients. After 1 year of treatment, ustekinumab and the TNFi showed similar persistence (hazard ratio [HR] for stopping/switching treatment 0.82; 95% CI 0.60-1.13) and a similar proportion of patients achieving (on the Disease Activity Index for PsA) clinical low disease activity (odds ratio [OR] 0.80; 95% CI 0.57-1.10) and remission (OR 0.73; 95% CI 0.49-1.07), along with similar safety profiles. Thus in real-world studies, TNFi and ustekinumab seem to have similar effectiveness and safety.

Drug persistence between patients with psoriasis alone vs. those with PsA is also of interest. In a real-life study including 62 patients with psoriasis and 90 patients with PsA who initiated treatment with secukinumab and were followed up for 24 months or until discontinuation, Ortolan and colleagues demonstrated that the retention rate of secukinumab was higher in psoriasis vs. PsA at 12 (85% vs. 68%) and 24 (61% vs. 57%) months, with the risk for secukinumab discontinuation being higher among patients with PsA in the overall cohort (HR 2.43; P = .035) and in patients with obesity in the PsA cohort (P = .021). Thus, the presence of PsA and obesity lower the secukinumab retention rate.

1. Despite the advent of many targeted therapies for PsA, there remain many unmet needs. Deucravacitinib is a novel oral selective inhibitor of tyrosine kinase 2 (TYK2) acting via binding to the TYK2 regulatory domain. In a phase 2 study including 203 patients with active PsA that was intolerant to at least one therapy who were randomly assigned to receive 6 mg deucravacitinib once daily, 12 mg deucravacitinib once daily, or placebo for 16 weeks, Mease and colleagues demonstrated that at week 16, American College of Rheumatology 20 (ACR20) response was significantly higher with 6 mg once-daily deucravacitinib (52.9%, adjusted OR [aOR] 2.4; P = .0134) and 12 mg (62.7%, aOR 3.6; P = .0004) vs. placebo (31.8%), with 12 mg deucravacitinib improving ACR20 response as early as at 8 weeks (P < .05). No serious adverse events were reported. Thus, TYK2 inhibition shows promise in the treatment of PsA and the results from phase 3 trials are awaited.

Vaccination strategies for people with rheumatic diseases have received significant scrutiny in regard to COVID-19 vaccines. People with rheumatoid arthritis (RA) are at higher risk for adverse outcomes related to COVID-19 but also may have reduced immunogenicity to COVID-19 vaccines; thus, temporary withdrawal of medications has been suggested. Renner Araujo and colleagues report the results of a single-center randomized study from Brazil looking at the immune response to two doses of the Sinovac-CoronaVac vaccine in 129 patients with RA. They found that those who stopped methotrexate for 2 weeks after both doses had a higher rate of seroconversion, based on immunoglobulin (Ig) G positivity (78% vs. 54%), than those who remained on methotrexate. Antibody titers were also higher in the "methotrexate-hold" group. Flare rates were higher, based on the Clinical Disease Activity Index (CDAI) — though not on the Disease Activity Scale-28 (DAS-28) — in patients who withdrew from methotrexate. This information is interesting with respect to the use of future inactivated virus vaccines, though its applicability to mRNA vaccines, other than predicting the possibility of flare, is less clear. However, the results could be useful in informed discussions and decision-making regarding withdrawing immunosuppressive drugs.

Some people with rheumatic diseases have been concerned about flares of disease activity related to COVID-19 vaccination. Tedeschi and colleagues conducted a prospective observational study of 71 patients with RA who were previously inoculated against COVID-19 with two mRNA vaccine doses or one adenovirus vector vaccine dose. Using the patient-reported Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5), they measured disease activity weekly from study enrollment through 4 weeks after an additional dose. They did not find any change in mean RADAI-5 score between pre- and post additional dose, nor was disease activity different in patients who stopped disease-modifying antirheumatic drugs (DMARD) compared with those who did not. The study also examined flow cytometry of lymphocyte populations among a subset of these patients (n = 27) and found no significant differences in T peripheral helper cells, T follicular helper cells, age-associated B cells, and plasmablasts among patients before and after the additional vaccine dose. Though the flow cytometry data are difficult to generalize, given the presumed heterogeneity and small number of patients, the lack of change in RA disease activity after the additional vaccine dose is reassuring.

Achievement of remission in patients with RA is also an area of continued interest, especially because of the difficulty of reaching this target under real-world conditions. Larid and colleagues report the prognostic factors of remission and characteristics of 215 patients with RA over 7 years of follow-up at an academic hospital in France. Notably, 33% of patients were in remission at 1 year, of whom 76% remained in remission at 7 years. However, 48% of patients who were not in remission at 1 year achieved remission at 7 years; 58% of study participants were in remission in total at 7 years of follow-up. Those in remission were more frequently being prescribed both conventional synthetic DMARD (csDMARD) and biologic DMARD (bDMARD), while those not in remission at 7 years were receiving corticosteroids at higher doses. Owing to the lack of more precise treatment information, as well as the large number of patients who did not complete the 7-year follow-up visit, drawing conclusions is difficult. While we cannot say, based on these results, that use of certain medication regimens or strategies is more likely to lead to remission, the data at least lend support to the possibility of achieving remission in the long term.

Finally, Ahmad and colleagues performed a post-hoc analysis of the phase 3b AVERT trial of abatacept vs. methotrexate; 172 patients in remission were evaluated at 6 and 12 months after withdrawal of abatacept + methotrexate, abatacept monotherapy, or methotrexate monotherapy. Similar proportions of patients in all three treatment groups experienced a flare (about 58% at 6 months and 66% at 12 months). Patients with higher Health Assessment Questionnaire Disability Index (HAQ-DI) scores and evidence of erosions on MRI at withdrawal were more likely to experience a flare, consistent with prior studies. This highlights potential predictors of withdrawal from therapy. Given the lack of significant difference between the treatment groups, however, it does raise the question of why combination therapy with abatacept and methotrexate is more likely to lead to patients achieving remission in studies without as big an effect on drug-free remission after withdrawal. A more stringent definition of remission rather than DAS-28 C-reactive protein may be desirable.

Vaccination strategies for people with rheumatic diseases have received significant scrutiny in regard to COVID-19 vaccines. People with rheumatoid arthritis (RA) are at higher risk for adverse outcomes related to COVID-19 but also may have reduced immunogenicity to COVID-19 vaccines; thus, temporary withdrawal of medications has been suggested. Renner Araujo and colleagues report the results of a single-center randomized study from Brazil looking at the immune response to two doses of the Sinovac-CoronaVac vaccine in 129 patients with RA. They found that those who stopped methotrexate for 2 weeks after both doses had a higher rate of seroconversion, based on immunoglobulin (Ig) G positivity (78% vs. 54%), than those who remained on methotrexate. Antibody titers were also higher in the "methotrexate-hold" group. Flare rates were higher, based on the Clinical Disease Activity Index (CDAI) — though not on the Disease Activity Scale-28 (DAS-28) — in patients who withdrew from methotrexate. This information is interesting with respect to the use of future inactivated virus vaccines, though its applicability to mRNA vaccines, other than predicting the possibility of flare, is less clear. However, the results could be useful in informed discussions and decision-making regarding withdrawing immunosuppressive drugs.

Some people with rheumatic diseases have been concerned about flares of disease activity related to COVID-19 vaccination. Tedeschi and colleagues conducted a prospective observational study of 71 patients with RA who were previously inoculated against COVID-19 with two mRNA vaccine doses or one adenovirus vector vaccine dose. Using the patient-reported Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5), they measured disease activity weekly from study enrollment through 4 weeks after an additional dose. They did not find any change in mean RADAI-5 score between pre- and post additional dose, nor was disease activity different in patients who stopped disease-modifying antirheumatic drugs (DMARD) compared with those who did not. The study also examined flow cytometry of lymphocyte populations among a subset of these patients (n = 27) and found no significant differences in T peripheral helper cells, T follicular helper cells, age-associated B cells, and plasmablasts among patients before and after the additional vaccine dose. Though the flow cytometry data are difficult to generalize, given the presumed heterogeneity and small number of patients, the lack of change in RA disease activity after the additional vaccine dose is reassuring.

Achievement of remission in patients with RA is also an area of continued interest, especially because of the difficulty of reaching this target under real-world conditions. Larid and colleagues report the prognostic factors of remission and characteristics of 215 patients with RA over 7 years of follow-up at an academic hospital in France. Notably, 33% of patients were in remission at 1 year, of whom 76% remained in remission at 7 years. However, 48% of patients who were not in remission at 1 year achieved remission at 7 years; 58% of study participants were in remission in total at 7 years of follow-up. Those in remission were more frequently being prescribed both conventional synthetic DMARD (csDMARD) and biologic DMARD (bDMARD), while those not in remission at 7 years were receiving corticosteroids at higher doses. Owing to the lack of more precise treatment information, as well as the large number of patients who did not complete the 7-year follow-up visit, drawing conclusions is difficult. While we cannot say, based on these results, that use of certain medication regimens or strategies is more likely to lead to remission, the data at least lend support to the possibility of achieving remission in the long term.

Finally, Ahmad and colleagues performed a post-hoc analysis of the phase 3b AVERT trial of abatacept vs. methotrexate; 172 patients in remission were evaluated at 6 and 12 months after withdrawal of abatacept + methotrexate, abatacept monotherapy, or methotrexate monotherapy. Similar proportions of patients in all three treatment groups experienced a flare (about 58% at 6 months and 66% at 12 months). Patients with higher Health Assessment Questionnaire Disability Index (HAQ-DI) scores and evidence of erosions on MRI at withdrawal were more likely to experience a flare, consistent with prior studies. This highlights potential predictors of withdrawal from therapy. Given the lack of significant difference between the treatment groups, however, it does raise the question of why combination therapy with abatacept and methotrexate is more likely to lead to patients achieving remission in studies without as big an effect on drug-free remission after withdrawal. A more stringent definition of remission rather than DAS-28 C-reactive protein may be desirable.

Vaccination strategies for people with rheumatic diseases have received significant scrutiny in regard to COVID-19 vaccines. People with rheumatoid arthritis (RA) are at higher risk for adverse outcomes related to COVID-19 but also may have reduced immunogenicity to COVID-19 vaccines; thus, temporary withdrawal of medications has been suggested. Renner Araujo and colleagues report the results of a single-center randomized study from Brazil looking at the immune response to two doses of the Sinovac-CoronaVac vaccine in 129 patients with RA. They found that those who stopped methotrexate for 2 weeks after both doses had a higher rate of seroconversion, based on immunoglobulin (Ig) G positivity (78% vs. 54%), than those who remained on methotrexate. Antibody titers were also higher in the "methotrexate-hold" group. Flare rates were higher, based on the Clinical Disease Activity Index (CDAI) — though not on the Disease Activity Scale-28 (DAS-28) — in patients who withdrew from methotrexate. This information is interesting with respect to the use of future inactivated virus vaccines, though its applicability to mRNA vaccines, other than predicting the possibility of flare, is less clear. However, the results could be useful in informed discussions and decision-making regarding withdrawing immunosuppressive drugs.

Some people with rheumatic diseases have been concerned about flares of disease activity related to COVID-19 vaccination. Tedeschi and colleagues conducted a prospective observational study of 71 patients with RA who were previously inoculated against COVID-19 with two mRNA vaccine doses or one adenovirus vector vaccine dose. Using the patient-reported Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5), they measured disease activity weekly from study enrollment through 4 weeks after an additional dose. They did not find any change in mean RADAI-5 score between pre- and post additional dose, nor was disease activity different in patients who stopped disease-modifying antirheumatic drugs (DMARD) compared with those who did not. The study also examined flow cytometry of lymphocyte populations among a subset of these patients (n = 27) and found no significant differences in T peripheral helper cells, T follicular helper cells, age-associated B cells, and plasmablasts among patients before and after the additional vaccine dose. Though the flow cytometry data are difficult to generalize, given the presumed heterogeneity and small number of patients, the lack of change in RA disease activity after the additional vaccine dose is reassuring.

Achievement of remission in patients with RA is also an area of continued interest, especially because of the difficulty of reaching this target under real-world conditions. Larid and colleagues report the prognostic factors of remission and characteristics of 215 patients with RA over 7 years of follow-up at an academic hospital in France. Notably, 33% of patients were in remission at 1 year, of whom 76% remained in remission at 7 years. However, 48% of patients who were not in remission at 1 year achieved remission at 7 years; 58% of study participants were in remission in total at 7 years of follow-up. Those in remission were more frequently being prescribed both conventional synthetic DMARD (csDMARD) and biologic DMARD (bDMARD), while those not in remission at 7 years were receiving corticosteroids at higher doses. Owing to the lack of more precise treatment information, as well as the large number of patients who did not complete the 7-year follow-up visit, drawing conclusions is difficult. While we cannot say, based on these results, that use of certain medication regimens or strategies is more likely to lead to remission, the data at least lend support to the possibility of achieving remission in the long term.

Finally, Ahmad and colleagues performed a post-hoc analysis of the phase 3b AVERT trial of abatacept vs. methotrexate; 172 patients in remission were evaluated at 6 and 12 months after withdrawal of abatacept + methotrexate, abatacept monotherapy, or methotrexate monotherapy. Similar proportions of patients in all three treatment groups experienced a flare (about 58% at 6 months and 66% at 12 months). Patients with higher Health Assessment Questionnaire Disability Index (HAQ-DI) scores and evidence of erosions on MRI at withdrawal were more likely to experience a flare, consistent with prior studies. This highlights potential predictors of withdrawal from therapy. Given the lack of significant difference between the treatment groups, however, it does raise the question of why combination therapy with abatacept and methotrexate is more likely to lead to patients achieving remission in studies without as big an effect on drug-free remission after withdrawal. A more stringent definition of remission rather than DAS-28 C-reactive protein may be desirable.

Yao and colleagues confirmed that there are well-known risk factors for recurrence of HCC after surgical resection. They retrospectively analyzed 1424 patients who underwent resection with curative intent for Barcelona Clinical Liver Cancer (BCLC) stage 0/A HCC in several centers in China. Of those patients, 679 (47.7%) developed recurrence at a median follow-up of 54.8 months, including 408 (60.1%) with an early recurrence (≤ 2 years after surgery) and 271 (39.9%) with a late recurrence (> 2 years). Cirrhosis (adjusted hazard ratio [aHR] 1.49; P < .001), preoperative alpha-fetoprotein (AFP) level > 400 µg/L (aHR 1.28; P = .004), tumor size > 5 cm (aHR 1.74; P < .001), the presence of satellite nodules (aHR 1.35; P = .040), multiple tumors (aHR 1.63; P = .015), microvascular invasion (aHR 1.51; P < .001), and intraoperative blood transfusion (aHR 1.50; P = .013) were identified as independent risk factors associated with postoperative HCC recurrence. The authors concluded that those patients with risk factors for recurrence would benefit from more intensive surveillance and potentially additional liver-directed therapy with curative intent.

Not all patients with hepatitis C virus (HCV) infection and HCC are offered antiviral therapy. Takaura and colleagues confirmed that active HCV infection worsens the prognosis of patients with very early-stage HCC who undergo treatment with radiofrequency ablation (RFA). In this single-center retrospective study, 302 patients with BCLC stage 0 HCC who underwent RFA were analyzed. Of those patients, 195 had evidence of HCV, and 132 had an active infection. The authors concluded that active HCV infection was a significant risk factor for shorter overall survival (aHR 2.17; P = .003) and early recurrence of HCC (aHR 1.47; P = .022). Patients with active HCV infection had a shorter median overall survival (66 months vs 145 months) and recurrence-free survival (20 months vs 31 months) (both P < .001). Therefore, treatment of active HCV should be offered to patients even after the development of HCC.

Kuroda and colleagues retrospectively analyzed a multicenter cohort of 247 patients with unresectable HCC treated with lenvatinib between 2018 and 2020. Out of those, 63 patients who received lenvatinib and transarterial chemoembolization (TACE) sequential therapy were propensity-score matched to those receiving lenvatinib monotherapy. The overall survival and progression-free survival in the sequential group were significantly higher than those in the lenvatinib monotherapy group, 31.2 (26.4-34.3) vs 15.7 (13.1-19.4) months and 12.2 (8.5-17.3) vs 6.7 (5.3-10.2) months (P = .002 and P = .037), respectively. Multivariate analysis showed that the deep response was independently associated with the initial response to levatinib; the partial response showed an odds ratio of 13.75 (95% CI 0.41-1.32; P < .001). The authors concluded that sequential therapy might provide more clinical benefits than lenvatinib monotherapy in patients who responded to initial lenvatinib treatment, with objective response to initial lenvatinib being an independent factor predicting sequential therapy deep response.

Yao and colleagues confirmed that there are well-known risk factors for recurrence of HCC after surgical resection. They retrospectively analyzed 1424 patients who underwent resection with curative intent for Barcelona Clinical Liver Cancer (BCLC) stage 0/A HCC in several centers in China. Of those patients, 679 (47.7%) developed recurrence at a median follow-up of 54.8 months, including 408 (60.1%) with an early recurrence (≤ 2 years after surgery) and 271 (39.9%) with a late recurrence (> 2 years). Cirrhosis (adjusted hazard ratio [aHR] 1.49; P < .001), preoperative alpha-fetoprotein (AFP) level > 400 µg/L (aHR 1.28; P = .004), tumor size > 5 cm (aHR 1.74; P < .001), the presence of satellite nodules (aHR 1.35; P = .040), multiple tumors (aHR 1.63; P = .015), microvascular invasion (aHR 1.51; P < .001), and intraoperative blood transfusion (aHR 1.50; P = .013) were identified as independent risk factors associated with postoperative HCC recurrence. The authors concluded that those patients with risk factors for recurrence would benefit from more intensive surveillance and potentially additional liver-directed therapy with curative intent.

Not all patients with hepatitis C virus (HCV) infection and HCC are offered antiviral therapy. Takaura and colleagues confirmed that active HCV infection worsens the prognosis of patients with very early-stage HCC who undergo treatment with radiofrequency ablation (RFA). In this single-center retrospective study, 302 patients with BCLC stage 0 HCC who underwent RFA were analyzed. Of those patients, 195 had evidence of HCV, and 132 had an active infection. The authors concluded that active HCV infection was a significant risk factor for shorter overall survival (aHR 2.17; P = .003) and early recurrence of HCC (aHR 1.47; P = .022). Patients with active HCV infection had a shorter median overall survival (66 months vs 145 months) and recurrence-free survival (20 months vs 31 months) (both P < .001). Therefore, treatment of active HCV should be offered to patients even after the development of HCC.

Kuroda and colleagues retrospectively analyzed a multicenter cohort of 247 patients with unresectable HCC treated with lenvatinib between 2018 and 2020. Out of those, 63 patients who received lenvatinib and transarterial chemoembolization (TACE) sequential therapy were propensity-score matched to those receiving lenvatinib monotherapy. The overall survival and progression-free survival in the sequential group were significantly higher than those in the lenvatinib monotherapy group, 31.2 (26.4-34.3) vs 15.7 (13.1-19.4) months and 12.2 (8.5-17.3) vs 6.7 (5.3-10.2) months (P = .002 and P = .037), respectively. Multivariate analysis showed that the deep response was independently associated with the initial response to levatinib; the partial response showed an odds ratio of 13.75 (95% CI 0.41-1.32; P < .001). The authors concluded that sequential therapy might provide more clinical benefits than lenvatinib monotherapy in patients who responded to initial lenvatinib treatment, with objective response to initial lenvatinib being an independent factor predicting sequential therapy deep response.

Yao and colleagues confirmed that there are well-known risk factors for recurrence of HCC after surgical resection. They retrospectively analyzed 1424 patients who underwent resection with curative intent for Barcelona Clinical Liver Cancer (BCLC) stage 0/A HCC in several centers in China. Of those patients, 679 (47.7%) developed recurrence at a median follow-up of 54.8 months, including 408 (60.1%) with an early recurrence (≤ 2 years after surgery) and 271 (39.9%) with a late recurrence (> 2 years). Cirrhosis (adjusted hazard ratio [aHR] 1.49; P < .001), preoperative alpha-fetoprotein (AFP) level > 400 µg/L (aHR 1.28; P = .004), tumor size > 5 cm (aHR 1.74; P < .001), the presence of satellite nodules (aHR 1.35; P = .040), multiple tumors (aHR 1.63; P = .015), microvascular invasion (aHR 1.51; P < .001), and intraoperative blood transfusion (aHR 1.50; P = .013) were identified as independent risk factors associated with postoperative HCC recurrence. The authors concluded that those patients with risk factors for recurrence would benefit from more intensive surveillance and potentially additional liver-directed therapy with curative intent.

Not all patients with hepatitis C virus (HCV) infection and HCC are offered antiviral therapy. Takaura and colleagues confirmed that active HCV infection worsens the prognosis of patients with very early-stage HCC who undergo treatment with radiofrequency ablation (RFA). In this single-center retrospective study, 302 patients with BCLC stage 0 HCC who underwent RFA were analyzed. Of those patients, 195 had evidence of HCV, and 132 had an active infection. The authors concluded that active HCV infection was a significant risk factor for shorter overall survival (aHR 2.17; P = .003) and early recurrence of HCC (aHR 1.47; P = .022). Patients with active HCV infection had a shorter median overall survival (66 months vs 145 months) and recurrence-free survival (20 months vs 31 months) (both P < .001). Therefore, treatment of active HCV should be offered to patients even after the development of HCC.

Kuroda and colleagues retrospectively analyzed a multicenter cohort of 247 patients with unresectable HCC treated with lenvatinib between 2018 and 2020. Out of those, 63 patients who received lenvatinib and transarterial chemoembolization (TACE) sequential therapy were propensity-score matched to those receiving lenvatinib monotherapy. The overall survival and progression-free survival in the sequential group were significantly higher than those in the lenvatinib monotherapy group, 31.2 (26.4-34.3) vs 15.7 (13.1-19.4) months and 12.2 (8.5-17.3) vs 6.7 (5.3-10.2) months (P = .002 and P = .037), respectively. Multivariate analysis showed that the deep response was independently associated with the initial response to levatinib; the partial response showed an odds ratio of 13.75 (95% CI 0.41-1.32; P < .001). The authors concluded that sequential therapy might provide more clinical benefits than lenvatinib monotherapy in patients who responded to initial lenvatinib treatment, with objective response to initial lenvatinib being an independent factor predicting sequential therapy deep response.

Yao and colleagues confirmed that there are well-known risk factors for recurrence of HCC after surgical resection. They retrospectively analyzed 1424 patients who underwent resection with curative intent for Barcelona Clinical Liver Cancer (BCLC) stage 0/A HCC in several centers in China. Of those patients, 679 (47.7%) developed recurrence at a median follow-up of 54.8 months, including 408 (60.1%) with an early recurrence (≤ 2 years after surgery) and 271 (39.9%) with a late recurrence (> 2 years). Cirrhosis (adjusted hazard ratio [aHR] 1.49; P < .001), preoperative alpha-fetoprotein (AFP) level > 400 µg/L (aHR 1.28; P = .004), tumor size > 5 cm (aHR 1.74; P < .001), the presence of satellite nodules (aHR 1.35; P = .040), multiple tumors (aHR 1.63; P = .015), microvascular invasion (aHR 1.51; P < .001), and intraoperative blood transfusion (aHR 1.50; P = .013) were identified as independent risk factors associated with postoperative HCC recurrence. The authors concluded that those patients with risk factors for recurrence would benefit from more intensive surveillance and potentially additional liver-directed therapy with curative intent.

Not all patients with hepatitis C virus (HCV) infection and HCC are offered antiviral therapy. Takaura and colleagues confirmed that active HCV infection worsens the prognosis of patients with very early-stage HCC who undergo treatment with radiofrequency ablation (RFA). In this single-center retrospective study, 302 patients with BCLC stage 0 HCC who underwent RFA were analyzed. Of those patients, 195 had evidence of HCV, and 132 had an active infection. The authors concluded that active HCV infection was a significant risk factor for shorter overall survival (aHR 2.17; P = .003) and early recurrence of HCC (aHR 1.47; P = .022). Patients with active HCV infection had a shorter median overall survival (66 months vs 145 months) and recurrence-free survival (20 months vs 31 months) (both P < .001). Therefore, treatment of active HCV should be offered to patients even after the development of HCC.

Kuroda and colleagues retrospectively analyzed a multicenter cohort of 247 patients with unresectable HCC treated with lenvatinib between 2018 and 2020. Out of those, 63 patients who received lenvatinib and transarterial chemoembolization (TACE) sequential therapy were propensity-score matched to those receiving lenvatinib monotherapy. The overall survival and progression-free survival in the sequential group were significantly higher than those in the lenvatinib monotherapy group, 31.2 (26.4-34.3) vs 15.7 (13.1-19.4) months and 12.2 (8.5-17.3) vs 6.7 (5.3-10.2) months (P = .002 and P = .037), respectively. Multivariate analysis showed that the deep response was independently associated with the initial response to levatinib; the partial response showed an odds ratio of 13.75 (95% CI 0.41-1.32; P < .001). The authors concluded that sequential therapy might provide more clinical benefits than lenvatinib monotherapy in patients who responded to initial lenvatinib treatment, with objective response to initial lenvatinib being an independent factor predicting sequential therapy deep response.

Yao and colleagues confirmed that there are well-known risk factors for recurrence of HCC after surgical resection. They retrospectively analyzed 1424 patients who underwent resection with curative intent for Barcelona Clinical Liver Cancer (BCLC) stage 0/A HCC in several centers in China. Of those patients, 679 (47.7%) developed recurrence at a median follow-up of 54.8 months, including 408 (60.1%) with an early recurrence (≤ 2 years after surgery) and 271 (39.9%) with a late recurrence (> 2 years). Cirrhosis (adjusted hazard ratio [aHR] 1.49; P < .001), preoperative alpha-fetoprotein (AFP) level > 400 µg/L (aHR 1.28; P = .004), tumor size > 5 cm (aHR 1.74; P < .001), the presence of satellite nodules (aHR 1.35; P = .040), multiple tumors (aHR 1.63; P = .015), microvascular invasion (aHR 1.51; P < .001), and intraoperative blood transfusion (aHR 1.50; P = .013) were identified as independent risk factors associated with postoperative HCC recurrence. The authors concluded that those patients with risk factors for recurrence would benefit from more intensive surveillance and potentially additional liver-directed therapy with curative intent.

Not all patients with hepatitis C virus (HCV) infection and HCC are offered antiviral therapy. Takaura and colleagues confirmed that active HCV infection worsens the prognosis of patients with very early-stage HCC who undergo treatment with radiofrequency ablation (RFA). In this single-center retrospective study, 302 patients with BCLC stage 0 HCC who underwent RFA were analyzed. Of those patients, 195 had evidence of HCV, and 132 had an active infection. The authors concluded that active HCV infection was a significant risk factor for shorter overall survival (aHR 2.17; P = .003) and early recurrence of HCC (aHR 1.47; P = .022). Patients with active HCV infection had a shorter median overall survival (66 months vs 145 months) and recurrence-free survival (20 months vs 31 months) (both P < .001). Therefore, treatment of active HCV should be offered to patients even after the development of HCC.

Kuroda and colleagues retrospectively analyzed a multicenter cohort of 247 patients with unresectable HCC treated with lenvatinib between 2018 and 2020. Out of those, 63 patients who received lenvatinib and transarterial chemoembolization (TACE) sequential therapy were propensity-score matched to those receiving lenvatinib monotherapy. The overall survival and progression-free survival in the sequential group were significantly higher than those in the lenvatinib monotherapy group, 31.2 (26.4-34.3) vs 15.7 (13.1-19.4) months and 12.2 (8.5-17.3) vs 6.7 (5.3-10.2) months (P = .002 and P = .037), respectively. Multivariate analysis showed that the deep response was independently associated with the initial response to levatinib; the partial response showed an odds ratio of 13.75 (95% CI 0.41-1.32; P < .001). The authors concluded that sequential therapy might provide more clinical benefits than lenvatinib monotherapy in patients who responded to initial lenvatinib treatment, with objective response to initial lenvatinib being an independent factor predicting sequential therapy deep response.

Yao and colleagues confirmed that there are well-known risk factors for recurrence of HCC after surgical resection. They retrospectively analyzed 1424 patients who underwent resection with curative intent for Barcelona Clinical Liver Cancer (BCLC) stage 0/A HCC in several centers in China. Of those patients, 679 (47.7%) developed recurrence at a median follow-up of 54.8 months, including 408 (60.1%) with an early recurrence (≤ 2 years after surgery) and 271 (39.9%) with a late recurrence (> 2 years). Cirrhosis (adjusted hazard ratio [aHR] 1.49; P < .001), preoperative alpha-fetoprotein (AFP) level > 400 µg/L (aHR 1.28; P = .004), tumor size > 5 cm (aHR 1.74; P < .001), the presence of satellite nodules (aHR 1.35; P = .040), multiple tumors (aHR 1.63; P = .015), microvascular invasion (aHR 1.51; P < .001), and intraoperative blood transfusion (aHR 1.50; P = .013) were identified as independent risk factors associated with postoperative HCC recurrence. The authors concluded that those patients with risk factors for recurrence would benefit from more intensive surveillance and potentially additional liver-directed therapy with curative intent.

Not all patients with hepatitis C virus (HCV) infection and HCC are offered antiviral therapy. Takaura and colleagues confirmed that active HCV infection worsens the prognosis of patients with very early-stage HCC who undergo treatment with radiofrequency ablation (RFA). In this single-center retrospective study, 302 patients with BCLC stage 0 HCC who underwent RFA were analyzed. Of those patients, 195 had evidence of HCV, and 132 had an active infection. The authors concluded that active HCV infection was a significant risk factor for shorter overall survival (aHR 2.17; P = .003) and early recurrence of HCC (aHR 1.47; P = .022). Patients with active HCV infection had a shorter median overall survival (66 months vs 145 months) and recurrence-free survival (20 months vs 31 months) (both P < .001). Therefore, treatment of active HCV should be offered to patients even after the development of HCC.

Kuroda and colleagues retrospectively analyzed a multicenter cohort of 247 patients with unresectable HCC treated with lenvatinib between 2018 and 2020. Out of those, 63 patients who received lenvatinib and transarterial chemoembolization (TACE) sequential therapy were propensity-score matched to those receiving lenvatinib monotherapy. The overall survival and progression-free survival in the sequential group were significantly higher than those in the lenvatinib monotherapy group, 31.2 (26.4-34.3) vs 15.7 (13.1-19.4) months and 12.2 (8.5-17.3) vs 6.7 (5.3-10.2) months (P = .002 and P = .037), respectively. Multivariate analysis showed that the deep response was independently associated with the initial response to levatinib; the partial response showed an odds ratio of 13.75 (95% CI 0.41-1.32; P < .001). The authors concluded that sequential therapy might provide more clinical benefits than lenvatinib monotherapy in patients who responded to initial lenvatinib treatment, with objective response to initial lenvatinib being an independent factor predicting sequential therapy deep response.

Studies have demonstrated inferior survival outcomes associated with delays in time to surgery and adjuvant chemotherapy for early breast cancer. The timing of adjuvant endocrine therapy is also notable because of the favorable effect on recurrence risk and survival with these agents in early HR+ breast cancer. A cohort study from the National Cancer Database including 144,103 women demonstrated a 31% increase in the risk for death (hazard ratio [HR] 1.31; P < .001) with a time to adjuvant hormone therapy (TTH) > 150 days (6.4% of patients) compared with those with TTH ≤ 150 days (93.6% of patients). Factors associated with delay in TTH included Black race, nonprivate insurance, metropolitan residence (vs. urban or rural), community hospital setting (vs. academic), higher comorbidity index, poorly differentiated tumors, higher stage, breast conservation surgery (vs. mastectomy), and radiation therapy. This study highlights the need to avoid unnecessary delays in adjuvant hormone therapy and encourages further exploration of barriers to timely initiation of breast cancer therapies to maximize outcomes for patients.

The role of reproductive hormones in breast cancer risk and carcinogenesis has been extensively studied and hormonal therapies are an essential component of the management of HR+ breast cancer. Lan and colleagues performed a retrospective analysis including 196 premenopausal and 137 postmenopausal women treated with neoadjuvant chemotherapy for breast cancer, investigating the correlation between pretreatment levels of reproductive hormone levels with pathologic and survival outcomes. Higher likelihood of achieving pathologic complete response was seen in premenopausal women with lower vs. higher testosterone levels (odds ratio [OR] 0.996; P = .026) and in postmenopausal women with higher vs. lower follicle-stimulating hormone levels (OR 1.045; P = .005). Furthermore, lower progesterone levels in premenopausal patients was associated with inferior overall survival (OS) (3-year OS 72.9% vs. 97.4% for lowest tertile progesterone vs. higher tertiles; P = .007). These data suggest a potential role of reproductive hormones in the preoperative evaluation for breast cancer patients. Also, the complex actions of progesterone and "crosstalk" between estrogen receptors and progesterone receptors continue to be elucidated and ongoing studies are evaluating progestin combined with endocrine therapy.

The CLEOPATRA trial has established the regimen of trastuzumab plus pertuzumab plus docetaxel as first-line therapy for metastatic HER2-positive (HER2+) breast cancer with an absolute survival benefit of 16.3 months vs. trastuzumab plus docetaxel. A retrospective study conducted in Ontario, Canada, explored real-world outcomes of pertuzumab plus trastuzumab plus chemotherapy among 1158 patients and demonstrated a similar magnitude of survival improvement with the addition of pertuzumab (14.9 months) (Dai et al). The median OS was higher among patients receiving pertuzumab compared with control (40.2 vs. 25.3 months), and although the median OS was shorter in the real-world setting than in the CLEOPATRA trial, they had similar HRs for mortality reduction (0.66 for real-world and 0.69 for trial). Furthermore, there was no increase in cardiotoxicity and lower cumulative incidence of hospitalization at 1 year with pertuzumab vs. control (11.7% vs. 19.0%; P < .001). This study adds to the existing body of data supporting first-line treatment with pertuzumab plus trastuzumab plus chemotherapy for metastatic HER2+ breast cancer. The treatment landscape for these patients is certainly dynamic with the development of novel therapies and combinations in this space and resultant shifts in the current algorithm.

Recommended Additional Reading:

Hortobagyi GN et al. LBA17 Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32:S1290-S1291. Doi: 10.1016/j.annonc.2021.08.2090

Chavez-MacGregor M et al. Delayed initiation of adjuvant chemotherapy among patients with breast cancer. JAMA Oncol. 2016;2:322-329. Doi:10.1001/jamaoncol.2015.3856

Trabert B et al. Progesterone and breast cancer. Endocr Rev. 2020;41:320-344. Doi: 10.1210/endrev/bnz001

Swain SM et al; on behalf of the CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519-530. Doi: 10.1016/S1470-2045(19)30863-0

Studies have demonstrated inferior survival outcomes associated with delays in time to surgery and adjuvant chemotherapy for early breast cancer. The timing of adjuvant endocrine therapy is also notable because of the favorable effect on recurrence risk and survival with these agents in early HR+ breast cancer. A cohort study from the National Cancer Database including 144,103 women demonstrated a 31% increase in the risk for death (hazard ratio [HR] 1.31; P < .001) with a time to adjuvant hormone therapy (TTH) > 150 days (6.4% of patients) compared with those with TTH ≤ 150 days (93.6% of patients). Factors associated with delay in TTH included Black race, nonprivate insurance, metropolitan residence (vs. urban or rural), community hospital setting (vs. academic), higher comorbidity index, poorly differentiated tumors, higher stage, breast conservation surgery (vs. mastectomy), and radiation therapy. This study highlights the need to avoid unnecessary delays in adjuvant hormone therapy and encourages further exploration of barriers to timely initiation of breast cancer therapies to maximize outcomes for patients.

The role of reproductive hormones in breast cancer risk and carcinogenesis has been extensively studied and hormonal therapies are an essential component of the management of HR+ breast cancer. Lan and colleagues performed a retrospective analysis including 196 premenopausal and 137 postmenopausal women treated with neoadjuvant chemotherapy for breast cancer, investigating the correlation between pretreatment levels of reproductive hormone levels with pathologic and survival outcomes. Higher likelihood of achieving pathologic complete response was seen in premenopausal women with lower vs. higher testosterone levels (odds ratio [OR] 0.996; P = .026) and in postmenopausal women with higher vs. lower follicle-stimulating hormone levels (OR 1.045; P = .005). Furthermore, lower progesterone levels in premenopausal patients was associated with inferior overall survival (OS) (3-year OS 72.9% vs. 97.4% for lowest tertile progesterone vs. higher tertiles; P = .007). These data suggest a potential role of reproductive hormones in the preoperative evaluation for breast cancer patients. Also, the complex actions of progesterone and "crosstalk" between estrogen receptors and progesterone receptors continue to be elucidated and ongoing studies are evaluating progestin combined with endocrine therapy.

The CLEOPATRA trial has established the regimen of trastuzumab plus pertuzumab plus docetaxel as first-line therapy for metastatic HER2-positive (HER2+) breast cancer with an absolute survival benefit of 16.3 months vs. trastuzumab plus docetaxel. A retrospective study conducted in Ontario, Canada, explored real-world outcomes of pertuzumab plus trastuzumab plus chemotherapy among 1158 patients and demonstrated a similar magnitude of survival improvement with the addition of pertuzumab (14.9 months) (Dai et al). The median OS was higher among patients receiving pertuzumab compared with control (40.2 vs. 25.3 months), and although the median OS was shorter in the real-world setting than in the CLEOPATRA trial, they had similar HRs for mortality reduction (0.66 for real-world and 0.69 for trial). Furthermore, there was no increase in cardiotoxicity and lower cumulative incidence of hospitalization at 1 year with pertuzumab vs. control (11.7% vs. 19.0%; P < .001). This study adds to the existing body of data supporting first-line treatment with pertuzumab plus trastuzumab plus chemotherapy for metastatic HER2+ breast cancer. The treatment landscape for these patients is certainly dynamic with the development of novel therapies and combinations in this space and resultant shifts in the current algorithm.

Recommended Additional Reading:

Hortobagyi GN et al. LBA17 Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32:S1290-S1291. Doi: 10.1016/j.annonc.2021.08.2090

Chavez-MacGregor M et al. Delayed initiation of adjuvant chemotherapy among patients with breast cancer. JAMA Oncol. 2016;2:322-329. Doi:10.1001/jamaoncol.2015.3856

Trabert B et al. Progesterone and breast cancer. Endocr Rev. 2020;41:320-344. Doi: 10.1210/endrev/bnz001

Swain SM et al; on behalf of the CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519-530. Doi: 10.1016/S1470-2045(19)30863-0

Studies have demonstrated inferior survival outcomes associated with delays in time to surgery and adjuvant chemotherapy for early breast cancer. The timing of adjuvant endocrine therapy is also notable because of the favorable effect on recurrence risk and survival with these agents in early HR+ breast cancer. A cohort study from the National Cancer Database including 144,103 women demonstrated a 31% increase in the risk for death (hazard ratio [HR] 1.31; P < .001) with a time to adjuvant hormone therapy (TTH) > 150 days (6.4% of patients) compared with those with TTH ≤ 150 days (93.6% of patients). Factors associated with delay in TTH included Black race, nonprivate insurance, metropolitan residence (vs. urban or rural), community hospital setting (vs. academic), higher comorbidity index, poorly differentiated tumors, higher stage, breast conservation surgery (vs. mastectomy), and radiation therapy. This study highlights the need to avoid unnecessary delays in adjuvant hormone therapy and encourages further exploration of barriers to timely initiation of breast cancer therapies to maximize outcomes for patients.

The role of reproductive hormones in breast cancer risk and carcinogenesis has been extensively studied and hormonal therapies are an essential component of the management of HR+ breast cancer. Lan and colleagues performed a retrospective analysis including 196 premenopausal and 137 postmenopausal women treated with neoadjuvant chemotherapy for breast cancer, investigating the correlation between pretreatment levels of reproductive hormone levels with pathologic and survival outcomes. Higher likelihood of achieving pathologic complete response was seen in premenopausal women with lower vs. higher testosterone levels (odds ratio [OR] 0.996; P = .026) and in postmenopausal women with higher vs. lower follicle-stimulating hormone levels (OR 1.045; P = .005). Furthermore, lower progesterone levels in premenopausal patients was associated with inferior overall survival (OS) (3-year OS 72.9% vs. 97.4% for lowest tertile progesterone vs. higher tertiles; P = .007). These data suggest a potential role of reproductive hormones in the preoperative evaluation for breast cancer patients. Also, the complex actions of progesterone and "crosstalk" between estrogen receptors and progesterone receptors continue to be elucidated and ongoing studies are evaluating progestin combined with endocrine therapy.

The CLEOPATRA trial has established the regimen of trastuzumab plus pertuzumab plus docetaxel as first-line therapy for metastatic HER2-positive (HER2+) breast cancer with an absolute survival benefit of 16.3 months vs. trastuzumab plus docetaxel. A retrospective study conducted in Ontario, Canada, explored real-world outcomes of pertuzumab plus trastuzumab plus chemotherapy among 1158 patients and demonstrated a similar magnitude of survival improvement with the addition of pertuzumab (14.9 months) (Dai et al). The median OS was higher among patients receiving pertuzumab compared with control (40.2 vs. 25.3 months), and although the median OS was shorter in the real-world setting than in the CLEOPATRA trial, they had similar HRs for mortality reduction (0.66 for real-world and 0.69 for trial). Furthermore, there was no increase in cardiotoxicity and lower cumulative incidence of hospitalization at 1 year with pertuzumab vs. control (11.7% vs. 19.0%; P < .001). This study adds to the existing body of data supporting first-line treatment with pertuzumab plus trastuzumab plus chemotherapy for metastatic HER2+ breast cancer. The treatment landscape for these patients is certainly dynamic with the development of novel therapies and combinations in this space and resultant shifts in the current algorithm.

Recommended Additional Reading:

Hortobagyi GN et al. LBA17 Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32:S1290-S1291. Doi: 10.1016/j.annonc.2021.08.2090

Chavez-MacGregor M et al. Delayed initiation of adjuvant chemotherapy among patients with breast cancer. JAMA Oncol. 2016;2:322-329. Doi:10.1001/jamaoncol.2015.3856

Trabert B et al. Progesterone and breast cancer. Endocr Rev. 2020;41:320-344. Doi: 10.1210/endrev/bnz001

Swain SM et al; on behalf of the CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519-530. Doi: 10.1016/S1470-2045(19)30863-0

Key clinical point: Curcumin consumption for 8 weeks as a part of an integrated approach could help modulate metabolic factors, inflammation, and adiposity in women with rheumatoid arthritis (RA).

Major finding: After 8 weeks, insulin resistance, erythrocyte sedimentation rate, serum levels of high-sensitivity C-reactive protein, and triglycerides improved significantly in the curcumin supplementation vs. placebo group (all P < .05). Moreover, curcumin supplementation significantly decreased mean weight, body mass index, and waist circumference by 0.45% (P < .001), 0.57% (P = .003), and 0.23% (P = .008), respectively, vs. no significant changes observed in placebo group.

Study details: The findings come from a randomized, double-blind, placebo-controlled clinical trial including 44 women with RA randomly assigned to either curcumin supplementation (500 mg/day; n = 22) or placebo (n = 22) for 8 weeks.

Disclosures: This study was supported by Research Vice-Chancellor and Nutrition Research Center of Tabriz University of Medical Sciences, Tabriz, Iran. The authors declared no conflicts of interest.

Source: Pourhabibi-Zarandi F et al. Effects of curcumin supplementation on metabolic parameters, inflammatory factors and obesity values in women with rheumatoid arthritis: A randomized, double-blind, placebo-controlled clinical trial. Phytother Res. 2022 (Feb 17). Doi: 10.1002/ptr.7422

Key clinical point: Curcumin consumption for 8 weeks as a part of an integrated approach could help modulate metabolic factors, inflammation, and adiposity in women with rheumatoid arthritis (RA).

Major finding: After 8 weeks, insulin resistance, erythrocyte sedimentation rate, serum levels of high-sensitivity C-reactive protein, and triglycerides improved significantly in the curcumin supplementation vs. placebo group (all P < .05). Moreover, curcumin supplementation significantly decreased mean weight, body mass index, and waist circumference by 0.45% (P < .001), 0.57% (P = .003), and 0.23% (P = .008), respectively, vs. no significant changes observed in placebo group.

Study details: The findings come from a randomized, double-blind, placebo-controlled clinical trial including 44 women with RA randomly assigned to either curcumin supplementation (500 mg/day; n = 22) or placebo (n = 22) for 8 weeks.

Disclosures: This study was supported by Research Vice-Chancellor and Nutrition Research Center of Tabriz University of Medical Sciences, Tabriz, Iran. The authors declared no conflicts of interest.

Source: Pourhabibi-Zarandi F et al. Effects of curcumin supplementation on metabolic parameters, inflammatory factors and obesity values in women with rheumatoid arthritis: A randomized, double-blind, placebo-controlled clinical trial. Phytother Res. 2022 (Feb 17). Doi: 10.1002/ptr.7422

Key clinical point: Curcumin consumption for 8 weeks as a part of an integrated approach could help modulate metabolic factors, inflammation, and adiposity in women with rheumatoid arthritis (RA).

Major finding: After 8 weeks, insulin resistance, erythrocyte sedimentation rate, serum levels of high-sensitivity C-reactive protein, and triglycerides improved significantly in the curcumin supplementation vs. placebo group (all P < .05). Moreover, curcumin supplementation significantly decreased mean weight, body mass index, and waist circumference by 0.45% (P < .001), 0.57% (P = .003), and 0.23% (P = .008), respectively, vs. no significant changes observed in placebo group.

Study details: The findings come from a randomized, double-blind, placebo-controlled clinical trial including 44 women with RA randomly assigned to either curcumin supplementation (500 mg/day; n = 22) or placebo (n = 22) for 8 weeks.

Disclosures: This study was supported by Research Vice-Chancellor and Nutrition Research Center of Tabriz University of Medical Sciences, Tabriz, Iran. The authors declared no conflicts of interest.

Source: Pourhabibi-Zarandi F et al. Effects of curcumin supplementation on metabolic parameters, inflammatory factors and obesity values in women with rheumatoid arthritis: A randomized, double-blind, placebo-controlled clinical trial. Phytother Res. 2022 (Feb 17). Doi: 10.1002/ptr.7422

Key clinical point: Fostamatinib use in patients with rheumatoid arthritis (RA) was not associated with an overall increased risk of developing neoplasms compared with placebo. However, prolonged use may raise the risk for malignant neoplasms.

Major finding: Fostamatinib vs. placebo was not associated with an increased risk for total neoplasms (Peto odds ratio [OR] 2.62; 95% CI 0.97-7.10), malignant neoplasms (Peto OR 3.08; 95% CI 0.96-9.91), or benign neoplasms (Peto OR 1.71; 95% CI 0.26-11.36). However, long-term fostamatinib treatment vs. placebo was associated with a higher risk for malignant neoplasms at 52 weeks (Peto OR 4.49; 95% CI 1.03-19.60).

Study details: This was a meta-analysis of seven trials including 4,971 patients with RA treated with fostamatinib.

Disclosures: This study was supported by Post-doctoral Research and Development Fund of West China Hospital of Sichuan University and others. The authors declared no conflict of interests.

Source: Chan Y et al. Neoplasm risk in patients with rheumatoid arthritis treated with fostamatinib: A systematic review and meta-analysis. Front Pharmacol. 2022;13:768980 (Mar 2). Doi: 10.3389/fphar.2022.768980

Key clinical point: Fostamatinib use in patients with rheumatoid arthritis (RA) was not associated with an overall increased risk of developing neoplasms compared with placebo. However, prolonged use may raise the risk for malignant neoplasms.

Major finding: Fostamatinib vs. placebo was not associated with an increased risk for total neoplasms (Peto odds ratio [OR] 2.62; 95% CI 0.97-7.10), malignant neoplasms (Peto OR 3.08; 95% CI 0.96-9.91), or benign neoplasms (Peto OR 1.71; 95% CI 0.26-11.36). However, long-term fostamatinib treatment vs. placebo was associated with a higher risk for malignant neoplasms at 52 weeks (Peto OR 4.49; 95% CI 1.03-19.60).

Study details: This was a meta-analysis of seven trials including 4,971 patients with RA treated with fostamatinib.

Disclosures: This study was supported by Post-doctoral Research and Development Fund of West China Hospital of Sichuan University and others. The authors declared no conflict of interests.

Source: Chan Y et al. Neoplasm risk in patients with rheumatoid arthritis treated with fostamatinib: A systematic review and meta-analysis. Front Pharmacol. 2022;13:768980 (Mar 2). Doi: 10.3389/fphar.2022.768980

Key clinical point: Fostamatinib use in patients with rheumatoid arthritis (RA) was not associated with an overall increased risk of developing neoplasms compared with placebo. However, prolonged use may raise the risk for malignant neoplasms.

Major finding: Fostamatinib vs. placebo was not associated with an increased risk for total neoplasms (Peto odds ratio [OR] 2.62; 95% CI 0.97-7.10), malignant neoplasms (Peto OR 3.08; 95% CI 0.96-9.91), or benign neoplasms (Peto OR 1.71; 95% CI 0.26-11.36). However, long-term fostamatinib treatment vs. placebo was associated with a higher risk for malignant neoplasms at 52 weeks (Peto OR 4.49; 95% CI 1.03-19.60).

Study details: This was a meta-analysis of seven trials including 4,971 patients with RA treated with fostamatinib.

Disclosures: This study was supported by Post-doctoral Research and Development Fund of West China Hospital of Sichuan University and others. The authors declared no conflict of interests.

Source: Chan Y et al. Neoplasm risk in patients with rheumatoid arthritis treated with fostamatinib: A systematic review and meta-analysis. Front Pharmacol. 2022;13:768980 (Mar 2). Doi: 10.3389/fphar.2022.768980