Clinical Edge Journal Scan

It is well known that the best outcomes for patients with rheumatoid arthritis (RA) are achieved with a treat-to-target strategy, but recent research has also focused on tapering therapy, especially biologics, in patients who are in prolonged disease remission without synovitis. In the open-label, randomized, noninferiority ARCTIC REWIND trial, Lillegraven and colleagues looked at the effects of tapering tumor necrosis factor inhibitors (TNFi) in 84 patients at different sites in Norway. Patients who had been in remission for a year or more on stable therapy (including TNFi and conventional synthetic disease-modifying antirheumatic drugs [csDMARD]) were included in the study. Of the 43 randomly assigned to tapering TNFi therapy, nearly two-thirds had a flare in 12 months of follow-up, compared with 5% in the stable TNFi group; thus, noninferiority of tapering TNFi was not supported. This study is small and seems to highlight a greater disparity between the two groups than expected from prior studies. Given the stark difference between the two groups, however, caution is advised in tapering TNFi therapy in patients with RA, even those in "deep remission." This information is reassuring in that most patients who flared had a good response to reinstating TNFi therapy, and it is helpful in counseling patients who prefer to try to reduce their medication burden despite the potential for flare.

The impact of chronic steroid use in RA has also received a lot of scrutiny in recent literature due to possible long-term side effects such as bone loss, hyperglycemia, and accelerated atherosclerotic disease. Palmowski and colleagues conducted a pooled analysis of several European randomized trials comparing the use of low-dose glucocorticoids (< 7.5 mg/d prednisone) vs placebo in combination with targeted therapy for RA. Data from over 1100 patients in five trials were analyzed. Over the course of 2 years, participants in both groups had gained weight, more so in the glucocorticoid group compared with the control group (1.8 kg vs 0.7 kg), with negligible effects on blood pressure. While use of moderate and high doses of glucocorticoids is not advisable for the long term, the use of low doses appears to be tolerable, with relatively minor effects on weight and blood pressure.

Given the chronic nature of RA and increasing incidence with age, comorbidities and multimorbidity (two or more comorbidities) are common in patients with RA. Stevens and colleagues used a national claims database to examine the burden of multimorbidity in people with RA and its association with sex and age in two different age groups (18-50 years and older than 51 years). Over 154,000 patients with RA were matched 1:1 to those without. The risk for multimorbidity was higher in women vs men with RA, though the absolute difference in risk was not large. The magnitude of these differences (between women and men, and between those with and without RA) was more pronounced in the younger age group and, as expected, decreased in the older age group. Of note, men with RA, compared with women with RA, had a higher risk for cardiovascular disease, including hypertension, high cholesterol, coronary artery disease, valvular disease, and heart failure. Women with RA had more psychological, neurologic, and comorbid noninflammatory musculoskeletal conditions, such as chronic lower back pain. These differences stress the need for attention to individualized care to improve patients' quality of life and reduce adverse effects on other areas of health.

It is well known that the best outcomes for patients with rheumatoid arthritis (RA) are achieved with a treat-to-target strategy, but recent research has also focused on tapering therapy, especially biologics, in patients who are in prolonged disease remission without synovitis. In the open-label, randomized, noninferiority ARCTIC REWIND trial, Lillegraven and colleagues looked at the effects of tapering tumor necrosis factor inhibitors (TNFi) in 84 patients at different sites in Norway. Patients who had been in remission for a year or more on stable therapy (including TNFi and conventional synthetic disease-modifying antirheumatic drugs [csDMARD]) were included in the study. Of the 43 randomly assigned to tapering TNFi therapy, nearly two-thirds had a flare in 12 months of follow-up, compared with 5% in the stable TNFi group; thus, noninferiority of tapering TNFi was not supported. This study is small and seems to highlight a greater disparity between the two groups than expected from prior studies. Given the stark difference between the two groups, however, caution is advised in tapering TNFi therapy in patients with RA, even those in "deep remission." This information is reassuring in that most patients who flared had a good response to reinstating TNFi therapy, and it is helpful in counseling patients who prefer to try to reduce their medication burden despite the potential for flare.

The impact of chronic steroid use in RA has also received a lot of scrutiny in recent literature due to possible long-term side effects such as bone loss, hyperglycemia, and accelerated atherosclerotic disease. Palmowski and colleagues conducted a pooled analysis of several European randomized trials comparing the use of low-dose glucocorticoids (< 7.5 mg/d prednisone) vs placebo in combination with targeted therapy for RA. Data from over 1100 patients in five trials were analyzed. Over the course of 2 years, participants in both groups had gained weight, more so in the glucocorticoid group compared with the control group (1.8 kg vs 0.7 kg), with negligible effects on blood pressure. While use of moderate and high doses of glucocorticoids is not advisable for the long term, the use of low doses appears to be tolerable, with relatively minor effects on weight and blood pressure.

Given the chronic nature of RA and increasing incidence with age, comorbidities and multimorbidity (two or more comorbidities) are common in patients with RA. Stevens and colleagues used a national claims database to examine the burden of multimorbidity in people with RA and its association with sex and age in two different age groups (18-50 years and older than 51 years). Over 154,000 patients with RA were matched 1:1 to those without. The risk for multimorbidity was higher in women vs men with RA, though the absolute difference in risk was not large. The magnitude of these differences (between women and men, and between those with and without RA) was more pronounced in the younger age group and, as expected, decreased in the older age group. Of note, men with RA, compared with women with RA, had a higher risk for cardiovascular disease, including hypertension, high cholesterol, coronary artery disease, valvular disease, and heart failure. Women with RA had more psychological, neurologic, and comorbid noninflammatory musculoskeletal conditions, such as chronic lower back pain. These differences stress the need for attention to individualized care to improve patients' quality of life and reduce adverse effects on other areas of health.

It is well known that the best outcomes for patients with rheumatoid arthritis (RA) are achieved with a treat-to-target strategy, but recent research has also focused on tapering therapy, especially biologics, in patients who are in prolonged disease remission without synovitis. In the open-label, randomized, noninferiority ARCTIC REWIND trial, Lillegraven and colleagues looked at the effects of tapering tumor necrosis factor inhibitors (TNFi) in 84 patients at different sites in Norway. Patients who had been in remission for a year or more on stable therapy (including TNFi and conventional synthetic disease-modifying antirheumatic drugs [csDMARD]) were included in the study. Of the 43 randomly assigned to tapering TNFi therapy, nearly two-thirds had a flare in 12 months of follow-up, compared with 5% in the stable TNFi group; thus, noninferiority of tapering TNFi was not supported. This study is small and seems to highlight a greater disparity between the two groups than expected from prior studies. Given the stark difference between the two groups, however, caution is advised in tapering TNFi therapy in patients with RA, even those in "deep remission." This information is reassuring in that most patients who flared had a good response to reinstating TNFi therapy, and it is helpful in counseling patients who prefer to try to reduce their medication burden despite the potential for flare.

The impact of chronic steroid use in RA has also received a lot of scrutiny in recent literature due to possible long-term side effects such as bone loss, hyperglycemia, and accelerated atherosclerotic disease. Palmowski and colleagues conducted a pooled analysis of several European randomized trials comparing the use of low-dose glucocorticoids (< 7.5 mg/d prednisone) vs placebo in combination with targeted therapy for RA. Data from over 1100 patients in five trials were analyzed. Over the course of 2 years, participants in both groups had gained weight, more so in the glucocorticoid group compared with the control group (1.8 kg vs 0.7 kg), with negligible effects on blood pressure. While use of moderate and high doses of glucocorticoids is not advisable for the long term, the use of low doses appears to be tolerable, with relatively minor effects on weight and blood pressure.

Given the chronic nature of RA and increasing incidence with age, comorbidities and multimorbidity (two or more comorbidities) are common in patients with RA. Stevens and colleagues used a national claims database to examine the burden of multimorbidity in people with RA and its association with sex and age in two different age groups (18-50 years and older than 51 years). Over 154,000 patients with RA were matched 1:1 to those without. The risk for multimorbidity was higher in women vs men with RA, though the absolute difference in risk was not large. The magnitude of these differences (between women and men, and between those with and without RA) was more pronounced in the younger age group and, as expected, decreased in the older age group. Of note, men with RA, compared with women with RA, had a higher risk for cardiovascular disease, including hypertension, high cholesterol, coronary artery disease, valvular disease, and heart failure. Women with RA had more psychological, neurologic, and comorbid noninflammatory musculoskeletal conditions, such as chronic lower back pain. These differences stress the need for attention to individualized care to improve patients' quality of life and reduce adverse effects on other areas of health.

The treatment of mantle cell lymphoma (MCL) continues to evolve. In the front-line setting, studies are evaluating the role of novel therapies as well as consolidation with autologous stem cell transplantation. In the relapsed/refractory setting, patients can be considered for treatment with Bruton tyrosine kinase (BTK) inhibitors, other targeted therapies, or chimeric antigen receptor (CAR) T-cell therapy. Other novel therapies, including bispecific antibodies and novel antibody drug conjugates, are being studied as well.

Despite the availability of novel agents, a subset of patients continues to have difficult-to-treat disease and a poor prognosis. Established prognostic tools that aid in identifying high-risk patients include alternations in TP53, high proliferation rates, nonclassic morphology, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which incorporates age, performance status, lactate dehydrogenase levels, and white blood cell count. The Nordic study group recently published a paper which provides additional prognostic information beyond these known variables (Rodrigues et al). They examined MYC expression in a cohort of 251 patients with MCL and structural aberrations in MYC and MYC mRNA levels in a smaller cohort. They found that patients with tumors comprising 20% or more cells with MYC overexpression (MYC^high tumors) vs MYC^low tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04), when adjusted for additional high-risk features. Patients with tumors with concomitant MYC^high expression and TP53/p53 alterations vs MYC^low tumors had a particularly poor prognosis, with significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of only 0.9 years (both P < .001). Though MYC overexpression was rare, this study identified a high-risk group of patients, especially those harboring concurrent TP53 aberrations, that may benefit from novel treatment approaches.

Another study recently aimed to identify patients who are at risk for poor outcomes after treatment with brexucabtagene autoleucel (brexu-cel) infusion. Though brexu-cel is an active therapy for patients with relapsed/refractory MCL, there are known toxicities, including cytokine release syndrome, neurologic toxicity, and hematologic toxicity. Given the potential for prolonged cytopenias and immune suppression, patients are also at risk for severe infections, which currently represent the driving determinant of nonrelapse mortality.¹ The CAR-HEMATOTOX (HT) score was previously found to identify patients who are at increased risk for hematologic toxicity after CAR T-cell therapy in diffuse large B-cell lymphoma.² In the current multicenter observational study, which included 103 patients receiving brexu-cel, the authors reported an association between baseline HT score and outcome in MCL as well. Patients with high (2-7) vs low (0-1) HT scores had significantly longer median duration of severe neutropenia (P < .0001), higher rates of severe infections (P = .001), and lower overall response rates (P = .003). The HT score represented an independent predictor of poor progression-free (aHR 3.7; P < .001) and overall (aHR 5.6; P = .002) survival. This tool may provide a helpful guide when counseling patients on treatment options and allow for more personalized toxicity management.

Despite availability of BTK inhibitors and CAR T-cell therapy for patients with MCL, relapses remain common. As upregulation of phosphoinositide 3-kinase (PI3K) is known to play a critical role in lymphomagenesis, there has been interest in targeting this pathway across lymphoma subtypes. Though PI3K inhibitors have been found to be active agents, they have also been associated with poor tolerability and safety concerns. Parsaclisib is a selective PI3K delta inhibitor that showed encouraging data in the phase 1/2 study in patients with non-Hodgkin lymphoma.³ More recently, the phase 2 CITADEL-205 study, which included adult patients with relapsed or refractory MCL previously treated with one to three systemic therapies, with (n = 53) or without (n = 108) prior BTK inhibitor treatment, was published (Zinazni et al). Patients received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily. Among BTK inhibitor–naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 months (95% CI 9.0 to not evaluable). Responses were not thought to be clinically meaningful in the patients treated with prior BTK inhibitors. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions. A total of 30% of patients required drug discontinuation due to adverse events. Though parsaclisib demonstrated activity in patients with relapsed/refractory MCL, the role of this drug in clinical practice is not clear given the increased use of BTK inhibitors as a preferred second-line therapy and ongoing concerns regarding PI3K inhibitor-related toxicity.

Additional References

1.      Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: Results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2023;41:2594-2606. doi: 10.1200/JCO.22.01797

2.      Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: A model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021;138:2499-2513. doi: 10.1182/blood.2020010543

3.      Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133:1742-1752. doi: 10.1182/blood-2018-08-867499

The treatment of mantle cell lymphoma (MCL) continues to evolve. In the front-line setting, studies are evaluating the role of novel therapies as well as consolidation with autologous stem cell transplantation. In the relapsed/refractory setting, patients can be considered for treatment with Bruton tyrosine kinase (BTK) inhibitors, other targeted therapies, or chimeric antigen receptor (CAR) T-cell therapy. Other novel therapies, including bispecific antibodies and novel antibody drug conjugates, are being studied as well.

Despite the availability of novel agents, a subset of patients continues to have difficult-to-treat disease and a poor prognosis. Established prognostic tools that aid in identifying high-risk patients include alternations in TP53, high proliferation rates, nonclassic morphology, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which incorporates age, performance status, lactate dehydrogenase levels, and white blood cell count. The Nordic study group recently published a paper which provides additional prognostic information beyond these known variables (Rodrigues et al). They examined MYC expression in a cohort of 251 patients with MCL and structural aberrations in MYC and MYC mRNA levels in a smaller cohort. They found that patients with tumors comprising 20% or more cells with MYC overexpression (MYC^high tumors) vs MYC^low tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04), when adjusted for additional high-risk features. Patients with tumors with concomitant MYC^high expression and TP53/p53 alterations vs MYC^low tumors had a particularly poor prognosis, with significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of only 0.9 years (both P < .001). Though MYC overexpression was rare, this study identified a high-risk group of patients, especially those harboring concurrent TP53 aberrations, that may benefit from novel treatment approaches.

Another study recently aimed to identify patients who are at risk for poor outcomes after treatment with brexucabtagene autoleucel (brexu-cel) infusion. Though brexu-cel is an active therapy for patients with relapsed/refractory MCL, there are known toxicities, including cytokine release syndrome, neurologic toxicity, and hematologic toxicity. Given the potential for prolonged cytopenias and immune suppression, patients are also at risk for severe infections, which currently represent the driving determinant of nonrelapse mortality.¹ The CAR-HEMATOTOX (HT) score was previously found to identify patients who are at increased risk for hematologic toxicity after CAR T-cell therapy in diffuse large B-cell lymphoma.² In the current multicenter observational study, which included 103 patients receiving brexu-cel, the authors reported an association between baseline HT score and outcome in MCL as well. Patients with high (2-7) vs low (0-1) HT scores had significantly longer median duration of severe neutropenia (P < .0001), higher rates of severe infections (P = .001), and lower overall response rates (P = .003). The HT score represented an independent predictor of poor progression-free (aHR 3.7; P < .001) and overall (aHR 5.6; P = .002) survival. This tool may provide a helpful guide when counseling patients on treatment options and allow for more personalized toxicity management.

Despite availability of BTK inhibitors and CAR T-cell therapy for patients with MCL, relapses remain common. As upregulation of phosphoinositide 3-kinase (PI3K) is known to play a critical role in lymphomagenesis, there has been interest in targeting this pathway across lymphoma subtypes. Though PI3K inhibitors have been found to be active agents, they have also been associated with poor tolerability and safety concerns. Parsaclisib is a selective PI3K delta inhibitor that showed encouraging data in the phase 1/2 study in patients with non-Hodgkin lymphoma.³ More recently, the phase 2 CITADEL-205 study, which included adult patients with relapsed or refractory MCL previously treated with one to three systemic therapies, with (n = 53) or without (n = 108) prior BTK inhibitor treatment, was published (Zinazni et al). Patients received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily. Among BTK inhibitor–naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 months (95% CI 9.0 to not evaluable). Responses were not thought to be clinically meaningful in the patients treated with prior BTK inhibitors. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions. A total of 30% of patients required drug discontinuation due to adverse events. Though parsaclisib demonstrated activity in patients with relapsed/refractory MCL, the role of this drug in clinical practice is not clear given the increased use of BTK inhibitors as a preferred second-line therapy and ongoing concerns regarding PI3K inhibitor-related toxicity.

Additional References

1.      Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: Results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2023;41:2594-2606. doi: 10.1200/JCO.22.01797

2.      Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: A model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021;138:2499-2513. doi: 10.1182/blood.2020010543

3.      Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133:1742-1752. doi: 10.1182/blood-2018-08-867499

The treatment of mantle cell lymphoma (MCL) continues to evolve. In the front-line setting, studies are evaluating the role of novel therapies as well as consolidation with autologous stem cell transplantation. In the relapsed/refractory setting, patients can be considered for treatment with Bruton tyrosine kinase (BTK) inhibitors, other targeted therapies, or chimeric antigen receptor (CAR) T-cell therapy. Other novel therapies, including bispecific antibodies and novel antibody drug conjugates, are being studied as well.

Despite the availability of novel agents, a subset of patients continues to have difficult-to-treat disease and a poor prognosis. Established prognostic tools that aid in identifying high-risk patients include alternations in TP53, high proliferation rates, nonclassic morphology, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which incorporates age, performance status, lactate dehydrogenase levels, and white blood cell count. The Nordic study group recently published a paper which provides additional prognostic information beyond these known variables (Rodrigues et al). They examined MYC expression in a cohort of 251 patients with MCL and structural aberrations in MYC and MYC mRNA levels in a smaller cohort. They found that patients with tumors comprising 20% or more cells with MYC overexpression (MYC^high tumors) vs MYC^low tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04), when adjusted for additional high-risk features. Patients with tumors with concomitant MYC^high expression and TP53/p53 alterations vs MYC^low tumors had a particularly poor prognosis, with significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of only 0.9 years (both P < .001). Though MYC overexpression was rare, this study identified a high-risk group of patients, especially those harboring concurrent TP53 aberrations, that may benefit from novel treatment approaches.

Another study recently aimed to identify patients who are at risk for poor outcomes after treatment with brexucabtagene autoleucel (brexu-cel) infusion. Though brexu-cel is an active therapy for patients with relapsed/refractory MCL, there are known toxicities, including cytokine release syndrome, neurologic toxicity, and hematologic toxicity. Given the potential for prolonged cytopenias and immune suppression, patients are also at risk for severe infections, which currently represent the driving determinant of nonrelapse mortality.¹ The CAR-HEMATOTOX (HT) score was previously found to identify patients who are at increased risk for hematologic toxicity after CAR T-cell therapy in diffuse large B-cell lymphoma.² In the current multicenter observational study, which included 103 patients receiving brexu-cel, the authors reported an association between baseline HT score and outcome in MCL as well. Patients with high (2-7) vs low (0-1) HT scores had significantly longer median duration of severe neutropenia (P < .0001), higher rates of severe infections (P = .001), and lower overall response rates (P = .003). The HT score represented an independent predictor of poor progression-free (aHR 3.7; P < .001) and overall (aHR 5.6; P = .002) survival. This tool may provide a helpful guide when counseling patients on treatment options and allow for more personalized toxicity management.

Despite availability of BTK inhibitors and CAR T-cell therapy for patients with MCL, relapses remain common. As upregulation of phosphoinositide 3-kinase (PI3K) is known to play a critical role in lymphomagenesis, there has been interest in targeting this pathway across lymphoma subtypes. Though PI3K inhibitors have been found to be active agents, they have also been associated with poor tolerability and safety concerns. Parsaclisib is a selective PI3K delta inhibitor that showed encouraging data in the phase 1/2 study in patients with non-Hodgkin lymphoma.³ More recently, the phase 2 CITADEL-205 study, which included adult patients with relapsed or refractory MCL previously treated with one to three systemic therapies, with (n = 53) or without (n = 108) prior BTK inhibitor treatment, was published (Zinazni et al). Patients received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily. Among BTK inhibitor–naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 months (95% CI 9.0 to not evaluable). Responses were not thought to be clinically meaningful in the patients treated with prior BTK inhibitors. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions. A total of 30% of patients required drug discontinuation due to adverse events. Though parsaclisib demonstrated activity in patients with relapsed/refractory MCL, the role of this drug in clinical practice is not clear given the increased use of BTK inhibitors as a preferred second-line therapy and ongoing concerns regarding PI3K inhibitor-related toxicity.

Additional References

1.      Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: Results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2023;41:2594-2606. doi: 10.1200/JCO.22.01797

2.      Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: A model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021;138:2499-2513. doi: 10.1182/blood.2020010543

3.      Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133:1742-1752. doi: 10.1182/blood-2018-08-867499

Endocrine therapy (ET) remains the backbone of treatment for hormone receptor–positive breast cancer; however, 15%-20% of tumors are initially resistant to ET and endocrine resistance develops over time in approximately 30%-40%.² In an effort to overcome limitations with historical standard-of-care endocrine agents, the class of oral potent selective estrogen receptor degraders (SERD) is evolving. The phase 2, randomized, controlled coopERA Breast Cancer trial evaluated the antiproliferative effect of giredestrant (a highly potent nonsteroidal oral SERD) compared with anastrozole (each combined with palbociclib after 2-week window-of-opportunity phase) among postmenopausal women with early-stage (cT1c-cT4) ER+/HER2- breast cancer with a Ki67 score ≥ 5% (Hurvitz et al). Among 221 enrolled patients (giredestrant group n = 112, and anastrozole group n = 109), giredestrant led to a significantly greater relative geometric mean reduction of Ki67 at 2 weeks from baseline compared with anastrozole (-75% vs -67%; P = 0.043). Neutropenia (26% and 27%) and decreased neutrophil count (15% and 15%) were the most common grade 3-4 adverse events in the giredestrant-palbociclib and anastrozole-palbociclib groups, respectively. The value of Ki67 as a biomarker for efficacy and outcome was demonstrated in the phase 3 POETIC trial, which showed that the degree of Ki67 reduction after 2 weeks of ET correlated with 5-year recurrence risk.³ These data encourage further investigation of oral SERD combinations, predictors of response, and long-term outcomes that may influence agent selection and sequencing.

Anticancer properties have been demonstrated with aspirin, statins, and metformin, although the data on the prognostic impact of these agents in breast cancer have shown mixed results.⁴ A nationwide population-based cohort study including 26,190 women aged 50 years or older diagnosed with breast cancer and surviving 12 months or more after diagnosis was performed to evaluate the postdiagnosis use of aspirin, statins, and metformin and association with breast cancer-specific survival (BCSS) (Löfling et al). At 6.1 years of follow-up, there were 2169 deaths related to breast cancer and the results supported an association of postdiagnostic use of statins and metformin with survival (hazard ratio for association between use of statins vs no use and BCSS was 0.84 [95% CI 0.75-0.94]; hazard ratio for association between metformin use vs use of nonmetformin antidiabetics and BCSS was 0.70 [95% CI 0.51-0.96]). Furthermore, there appeared to be differences in association by ER status. An important relationship exists between cardiovascular health and breast cancer, and future efforts should continue to study pharmacologic and lifestyle interventions that may optimize metabolic profiles and improve outcomes for patients.

Additional References

1. Kunkler IH, Williams LJ, Jack WJL, et al. Breast-conserving surgery with or without irradiation in early breast cancer. N Engl J Med. 2023;388:585-594. doi: 10.1056/NEJMoa2207586  
2. Lei JT, Anurag M, Haricharan S, et al. Endocrine therapy resistance: New insights. Breast. 2019;48:S26-S30. doi: 10.1016/S0960-9776(19)31118-X  
3. Smith I, Robertson J, Kilburn L, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): An open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020;21:1443-1454. doi: 10.1016/S1470-2045(20)30458-7
4. Nowakowska MK, Lei X, Thompson MT, et al. Association of statin use with clinical outcomes in patients with triple-negative breast cancer. Cancer. 2021;127:4142-4150. doi: 10.1002/cncr.33797

Endocrine therapy (ET) remains the backbone of treatment for hormone receptor–positive breast cancer; however, 15%-20% of tumors are initially resistant to ET and endocrine resistance develops over time in approximately 30%-40%.² In an effort to overcome limitations with historical standard-of-care endocrine agents, the class of oral potent selective estrogen receptor degraders (SERD) is evolving. The phase 2, randomized, controlled coopERA Breast Cancer trial evaluated the antiproliferative effect of giredestrant (a highly potent nonsteroidal oral SERD) compared with anastrozole (each combined with palbociclib after 2-week window-of-opportunity phase) among postmenopausal women with early-stage (cT1c-cT4) ER+/HER2- breast cancer with a Ki67 score ≥ 5% (Hurvitz et al). Among 221 enrolled patients (giredestrant group n = 112, and anastrozole group n = 109), giredestrant led to a significantly greater relative geometric mean reduction of Ki67 at 2 weeks from baseline compared with anastrozole (-75% vs -67%; P = 0.043). Neutropenia (26% and 27%) and decreased neutrophil count (15% and 15%) were the most common grade 3-4 adverse events in the giredestrant-palbociclib and anastrozole-palbociclib groups, respectively. The value of Ki67 as a biomarker for efficacy and outcome was demonstrated in the phase 3 POETIC trial, which showed that the degree of Ki67 reduction after 2 weeks of ET correlated with 5-year recurrence risk.³ These data encourage further investigation of oral SERD combinations, predictors of response, and long-term outcomes that may influence agent selection and sequencing.

Anticancer properties have been demonstrated with aspirin, statins, and metformin, although the data on the prognostic impact of these agents in breast cancer have shown mixed results.⁴ A nationwide population-based cohort study including 26,190 women aged 50 years or older diagnosed with breast cancer and surviving 12 months or more after diagnosis was performed to evaluate the postdiagnosis use of aspirin, statins, and metformin and association with breast cancer-specific survival (BCSS) (Löfling et al). At 6.1 years of follow-up, there were 2169 deaths related to breast cancer and the results supported an association of postdiagnostic use of statins and metformin with survival (hazard ratio for association between use of statins vs no use and BCSS was 0.84 [95% CI 0.75-0.94]; hazard ratio for association between metformin use vs use of nonmetformin antidiabetics and BCSS was 0.70 [95% CI 0.51-0.96]). Furthermore, there appeared to be differences in association by ER status. An important relationship exists between cardiovascular health and breast cancer, and future efforts should continue to study pharmacologic and lifestyle interventions that may optimize metabolic profiles and improve outcomes for patients.

Additional References

1. Kunkler IH, Williams LJ, Jack WJL, et al. Breast-conserving surgery with or without irradiation in early breast cancer. N Engl J Med. 2023;388:585-594. doi: 10.1056/NEJMoa2207586  
2. Lei JT, Anurag M, Haricharan S, et al. Endocrine therapy resistance: New insights. Breast. 2019;48:S26-S30. doi: 10.1016/S0960-9776(19)31118-X  
3. Smith I, Robertson J, Kilburn L, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): An open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020;21:1443-1454. doi: 10.1016/S1470-2045(20)30458-7
4. Nowakowska MK, Lei X, Thompson MT, et al. Association of statin use with clinical outcomes in patients with triple-negative breast cancer. Cancer. 2021;127:4142-4150. doi: 10.1002/cncr.33797

Endocrine therapy (ET) remains the backbone of treatment for hormone receptor–positive breast cancer; however, 15%-20% of tumors are initially resistant to ET and endocrine resistance develops over time in approximately 30%-40%.² In an effort to overcome limitations with historical standard-of-care endocrine agents, the class of oral potent selective estrogen receptor degraders (SERD) is evolving. The phase 2, randomized, controlled coopERA Breast Cancer trial evaluated the antiproliferative effect of giredestrant (a highly potent nonsteroidal oral SERD) compared with anastrozole (each combined with palbociclib after 2-week window-of-opportunity phase) among postmenopausal women with early-stage (cT1c-cT4) ER+/HER2- breast cancer with a Ki67 score ≥ 5% (Hurvitz et al). Among 221 enrolled patients (giredestrant group n = 112, and anastrozole group n = 109), giredestrant led to a significantly greater relative geometric mean reduction of Ki67 at 2 weeks from baseline compared with anastrozole (-75% vs -67%; P = 0.043). Neutropenia (26% and 27%) and decreased neutrophil count (15% and 15%) were the most common grade 3-4 adverse events in the giredestrant-palbociclib and anastrozole-palbociclib groups, respectively. The value of Ki67 as a biomarker for efficacy and outcome was demonstrated in the phase 3 POETIC trial, which showed that the degree of Ki67 reduction after 2 weeks of ET correlated with 5-year recurrence risk.³ These data encourage further investigation of oral SERD combinations, predictors of response, and long-term outcomes that may influence agent selection and sequencing.

Anticancer properties have been demonstrated with aspirin, statins, and metformin, although the data on the prognostic impact of these agents in breast cancer have shown mixed results.⁴ A nationwide population-based cohort study including 26,190 women aged 50 years or older diagnosed with breast cancer and surviving 12 months or more after diagnosis was performed to evaluate the postdiagnosis use of aspirin, statins, and metformin and association with breast cancer-specific survival (BCSS) (Löfling et al). At 6.1 years of follow-up, there were 2169 deaths related to breast cancer and the results supported an association of postdiagnostic use of statins and metformin with survival (hazard ratio for association between use of statins vs no use and BCSS was 0.84 [95% CI 0.75-0.94]; hazard ratio for association between metformin use vs use of nonmetformin antidiabetics and BCSS was 0.70 [95% CI 0.51-0.96]). Furthermore, there appeared to be differences in association by ER status. An important relationship exists between cardiovascular health and breast cancer, and future efforts should continue to study pharmacologic and lifestyle interventions that may optimize metabolic profiles and improve outcomes for patients.

Additional References

1. Kunkler IH, Williams LJ, Jack WJL, et al. Breast-conserving surgery with or without irradiation in early breast cancer. N Engl J Med. 2023;388:585-594. doi: 10.1056/NEJMoa2207586  
2. Lei JT, Anurag M, Haricharan S, et al. Endocrine therapy resistance: New insights. Breast. 2019;48:S26-S30. doi: 10.1016/S0960-9776(19)31118-X  
3. Smith I, Robertson J, Kilburn L, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): An open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020;21:1443-1454. doi: 10.1016/S1470-2045(20)30458-7
4. Nowakowska MK, Lei X, Thompson MT, et al. Association of statin use with clinical outcomes in patients with triple-negative breast cancer. Cancer. 2021;127:4142-4150. doi: 10.1002/cncr.33797

A recently published study by Rugo and colleagues presented the final analysis of overall survival and endpoints by trophoblast cell surface antigen 2 (Trop-2) expression. Results showed that at the 12.5-month median follow-up, sacituzumab govitecan vs chemotherapy improved overall survival by 3.2 months (hazard ratio 0.79; P = .020). The survival benefit was consistent across different levels of Trop-2 expression. No new adverse events were reported; however, one fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. These updated data continue to support the use of sacituzumab govitecan as a new treatment option for patients with endocrine-resistant HR+ and HER2- MBC.

It remains unclear whether anti-HER2 therapy alone (without chemotherapy) is an effective treatment approach for patients with ERBB2-positive MBC in the first-line setting. Huober and the Swiss Group for Clinical Cancer Research, the Unicancer Breast Group, and the Dutch Breast Cancer Research Group report a phase 2 trial that included 210 patients with ERBB2+ MBC who were randomly assigned to receive pertuzumab plus trastuzumab with or without chemotherapy followed by trastuzumab-emtansine as the second-line therapy in both groups. Despite worse progression-free survival in the nonchemotherapy vs the chemotherapy group (8.4 months [95% CI 7.9-12.0] vs 23.3 months [95% CI 18.9-33.1]), overall survival rates were comparable at 2 years of follow-up (79.0% [90% CI 71.4%-85.4%] vs 78.1% [90% CI 70.4%-84.5%]). Furthermore, adverse events were more frequent in the chemotherapy cohort, with small quality-of-life improvements from baseline in the nonchemotherapy cohort. Further prospective data are needed to confirm whether a chemotherapy-free approach is an acceptable treatment approach in certain population of patients, without unfavorable effects on overall survival.

Prior results from the SOFT and TEXT trials have shown improved survival with the addition of ovarian function suppression (OFS) in premenopausal women after chemotherapy. The ASTRRA trial is a similar phase 3 study that included 1282 premenopausal women with estrogen receptor–positive BC who remained premenopausal or regained ovarian function after chemotherapy and were randomly assigned to receive tamoxifen with or without OFS. The results showed a consistent disease-free survival benefit in women who received tamoxifen plus OFS vs tamoxifen alone (85.4% vs 80.2%; hazard ratio 0.67; P = .003) after a median follow-up of 8 years. There were no significant differences in 8-year OS rates between the two groups (P = .305), although both cohorts had high OS rates overall (> 95%). This trial highlights the overall excellent prognosis in this patient population and underscores the importance of OFS in the subgroup of patients who remain in a premenopausal state or resume ovarian function after chemotherapy.

The ICE study (Ibandronate with or without Capecitabine in Elderly patients with early breast cancer) was a phase 3 trial looking at 1358 patients age ≥ 65 years with node-positive or high-risk node-negative early BC who were randomly assigned to receive 2 years of ibandronate with or without capecitabine for six cycles in the adjuvant setting. At a median follow-up of 61 months, the 5-year invasive disease-free survival rates were similar amongst patients treated with adjuvant ibandronate plus capecitabine and ibandronate alone (hazard ratio 0.96; 95% CI 0.78-1.19). Outcomes were independent of age, nodal status, and hormone receptor status. The incidences of high-grade gastrointestinal disorders (6.7% vs 1.0%; P < .001) and skin toxicity (14.6% vs 0.6%; P < .01) were significantly higher in the capecitabine plus ibandronate arm vs the ibandronate alone arm.

Adjuvant capecitabine plus ibandronate failed to show improved survival outcomes compared with ibandronate alone in older patients with node-positive/high-risk node-negative BC. This was similar to results of the CALGB 49907 trial, which showed inferior survival for adjuvant capecitabine compared with standard adjuvant chemotherapy in patients ≥ 65 years of age.¹ Therefore, although oral capecitabine may be more tolerable than intravenous polychemotherapy in older patients with high-risk BC, this should be weighed against lower efficacy.

Additional Reference

1. Muss HB, Berry DA, Cirrincione CT, et al, for the CALGB Investigators. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009;360:2055-2065. doi: 10.1056/NEJMoa0810266

A recently published study by Rugo and colleagues presented the final analysis of overall survival and endpoints by trophoblast cell surface antigen 2 (Trop-2) expression. Results showed that at the 12.5-month median follow-up, sacituzumab govitecan vs chemotherapy improved overall survival by 3.2 months (hazard ratio 0.79; P = .020). The survival benefit was consistent across different levels of Trop-2 expression. No new adverse events were reported; however, one fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. These updated data continue to support the use of sacituzumab govitecan as a new treatment option for patients with endocrine-resistant HR+ and HER2- MBC.

It remains unclear whether anti-HER2 therapy alone (without chemotherapy) is an effective treatment approach for patients with ERBB2-positive MBC in the first-line setting. Huober and the Swiss Group for Clinical Cancer Research, the Unicancer Breast Group, and the Dutch Breast Cancer Research Group report a phase 2 trial that included 210 patients with ERBB2+ MBC who were randomly assigned to receive pertuzumab plus trastuzumab with or without chemotherapy followed by trastuzumab-emtansine as the second-line therapy in both groups. Despite worse progression-free survival in the nonchemotherapy vs the chemotherapy group (8.4 months [95% CI 7.9-12.0] vs 23.3 months [95% CI 18.9-33.1]), overall survival rates were comparable at 2 years of follow-up (79.0% [90% CI 71.4%-85.4%] vs 78.1% [90% CI 70.4%-84.5%]). Furthermore, adverse events were more frequent in the chemotherapy cohort, with small quality-of-life improvements from baseline in the nonchemotherapy cohort. Further prospective data are needed to confirm whether a chemotherapy-free approach is an acceptable treatment approach in certain population of patients, without unfavorable effects on overall survival.

Prior results from the SOFT and TEXT trials have shown improved survival with the addition of ovarian function suppression (OFS) in premenopausal women after chemotherapy. The ASTRRA trial is a similar phase 3 study that included 1282 premenopausal women with estrogen receptor–positive BC who remained premenopausal or regained ovarian function after chemotherapy and were randomly assigned to receive tamoxifen with or without OFS. The results showed a consistent disease-free survival benefit in women who received tamoxifen plus OFS vs tamoxifen alone (85.4% vs 80.2%; hazard ratio 0.67; P = .003) after a median follow-up of 8 years. There were no significant differences in 8-year OS rates between the two groups (P = .305), although both cohorts had high OS rates overall (> 95%). This trial highlights the overall excellent prognosis in this patient population and underscores the importance of OFS in the subgroup of patients who remain in a premenopausal state or resume ovarian function after chemotherapy.

The ICE study (Ibandronate with or without Capecitabine in Elderly patients with early breast cancer) was a phase 3 trial looking at 1358 patients age ≥ 65 years with node-positive or high-risk node-negative early BC who were randomly assigned to receive 2 years of ibandronate with or without capecitabine for six cycles in the adjuvant setting. At a median follow-up of 61 months, the 5-year invasive disease-free survival rates were similar amongst patients treated with adjuvant ibandronate plus capecitabine and ibandronate alone (hazard ratio 0.96; 95% CI 0.78-1.19). Outcomes were independent of age, nodal status, and hormone receptor status. The incidences of high-grade gastrointestinal disorders (6.7% vs 1.0%; P < .001) and skin toxicity (14.6% vs 0.6%; P < .01) were significantly higher in the capecitabine plus ibandronate arm vs the ibandronate alone arm.

Adjuvant capecitabine plus ibandronate failed to show improved survival outcomes compared with ibandronate alone in older patients with node-positive/high-risk node-negative BC. This was similar to results of the CALGB 49907 trial, which showed inferior survival for adjuvant capecitabine compared with standard adjuvant chemotherapy in patients ≥ 65 years of age.¹ Therefore, although oral capecitabine may be more tolerable than intravenous polychemotherapy in older patients with high-risk BC, this should be weighed against lower efficacy.

Additional Reference

1. Muss HB, Berry DA, Cirrincione CT, et al, for the CALGB Investigators. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009;360:2055-2065. doi: 10.1056/NEJMoa0810266

A recently published study by Rugo and colleagues presented the final analysis of overall survival and endpoints by trophoblast cell surface antigen 2 (Trop-2) expression. Results showed that at the 12.5-month median follow-up, sacituzumab govitecan vs chemotherapy improved overall survival by 3.2 months (hazard ratio 0.79; P = .020). The survival benefit was consistent across different levels of Trop-2 expression. No new adverse events were reported; however, one fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. These updated data continue to support the use of sacituzumab govitecan as a new treatment option for patients with endocrine-resistant HR+ and HER2- MBC.

It remains unclear whether anti-HER2 therapy alone (without chemotherapy) is an effective treatment approach for patients with ERBB2-positive MBC in the first-line setting. Huober and the Swiss Group for Clinical Cancer Research, the Unicancer Breast Group, and the Dutch Breast Cancer Research Group report a phase 2 trial that included 210 patients with ERBB2+ MBC who were randomly assigned to receive pertuzumab plus trastuzumab with or without chemotherapy followed by trastuzumab-emtansine as the second-line therapy in both groups. Despite worse progression-free survival in the nonchemotherapy vs the chemotherapy group (8.4 months [95% CI 7.9-12.0] vs 23.3 months [95% CI 18.9-33.1]), overall survival rates were comparable at 2 years of follow-up (79.0% [90% CI 71.4%-85.4%] vs 78.1% [90% CI 70.4%-84.5%]). Furthermore, adverse events were more frequent in the chemotherapy cohort, with small quality-of-life improvements from baseline in the nonchemotherapy cohort. Further prospective data are needed to confirm whether a chemotherapy-free approach is an acceptable treatment approach in certain population of patients, without unfavorable effects on overall survival.

Prior results from the SOFT and TEXT trials have shown improved survival with the addition of ovarian function suppression (OFS) in premenopausal women after chemotherapy. The ASTRRA trial is a similar phase 3 study that included 1282 premenopausal women with estrogen receptor–positive BC who remained premenopausal or regained ovarian function after chemotherapy and were randomly assigned to receive tamoxifen with or without OFS. The results showed a consistent disease-free survival benefit in women who received tamoxifen plus OFS vs tamoxifen alone (85.4% vs 80.2%; hazard ratio 0.67; P = .003) after a median follow-up of 8 years. There were no significant differences in 8-year OS rates between the two groups (P = .305), although both cohorts had high OS rates overall (> 95%). This trial highlights the overall excellent prognosis in this patient population and underscores the importance of OFS in the subgroup of patients who remain in a premenopausal state or resume ovarian function after chemotherapy.

The ICE study (Ibandronate with or without Capecitabine in Elderly patients with early breast cancer) was a phase 3 trial looking at 1358 patients age ≥ 65 years with node-positive or high-risk node-negative early BC who were randomly assigned to receive 2 years of ibandronate with or without capecitabine for six cycles in the adjuvant setting. At a median follow-up of 61 months, the 5-year invasive disease-free survival rates were similar amongst patients treated with adjuvant ibandronate plus capecitabine and ibandronate alone (hazard ratio 0.96; 95% CI 0.78-1.19). Outcomes were independent of age, nodal status, and hormone receptor status. The incidences of high-grade gastrointestinal disorders (6.7% vs 1.0%; P < .001) and skin toxicity (14.6% vs 0.6%; P < .01) were significantly higher in the capecitabine plus ibandronate arm vs the ibandronate alone arm.

Adjuvant capecitabine plus ibandronate failed to show improved survival outcomes compared with ibandronate alone in older patients with node-positive/high-risk node-negative BC. This was similar to results of the CALGB 49907 trial, which showed inferior survival for adjuvant capecitabine compared with standard adjuvant chemotherapy in patients ≥ 65 years of age.¹ Therefore, although oral capecitabine may be more tolerable than intravenous polychemotherapy in older patients with high-risk BC, this should be weighed against lower efficacy.

Additional Reference

1. Muss HB, Berry DA, Cirrincione CT, et al, for the CALGB Investigators. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009;360:2055-2065. doi: 10.1056/NEJMoa0810266

To address this gap in knowledge, Möller and colleagues compared the effectiveness of the first bDMARD in patients with PsA with low vs high joint counts (LJC and HJC, respectively). Using the Swiss Clinical Quality Management registry for rheumatic diseases, they obtained data on 387 patients with PsA who had either LJC (n = 197) or HJC (n = 190) and received bDMARD. As expected, patients with HJC had a higher burden of disease. Despite the higher burden, patients in both groups showed similar treatment efficacy in terms of drug retention. Consistent with previous reports, female sex was associated with lower treatment persistence, whereas concomitant treatment with conventional synthetic DMARD (csDMARD) was associated with longer bDMARD persistence. Thus, baseline joint counts may not be a good criterion for choosing who should be treated with bDMARD. The presence of active disease and lack of response to prior csDMARD is sufficient.

Persistence with therapy is an important indicator of drug effectiveness in the real world. A recent report from the CorEvitas registry by Mease and colleagues demonstrated that nearly 80% of patients with PsA persisted with guselkumab (an interleukin [IL]–23 inhibitor) treatment for 6 months and showed improvements in peripheral joint and skin symptoms. This study evaluated 114 patients with active PsA,  > 90% of whom were previously treated with b- and tsDMARD. The mean scores for clinical Disease Activity Index in PsA, overall joint and skin activity, patient-reported pain, and body surface area with psoriasis improved significantly.

Choosing the next therapy after lack of success with treatment with a tumour necrosis factor (TNF) inhibitor and an IL-17A inhibitor is difficult. One question is whether one should try another IL-17A inhibitor or move to another class of therapy. Hansen and colleagues tried to address this question by analyses of data from the Danish Rheumatology Registry. Patients with PsA who underwent prior treatment with one or more TNF inhibitor and switched to either first-line (n = 534) or second-line (n = 102) IL-17A inhibitors (ixekizumab or secukinumab) were included. Similar persistence with therapy was observed between first-line and second-line IL-17A inhibitor switchers and between second-line secukinumab and second-line ixekizumab switchers. Withdrawal reasons were similar for both first-line and second-line switchers when considering adverse events; however, withdrawal due to lack of successful therapy was higher for the first-line vs second-line switchers (34% vs 18%). An important piece of information missing in the report was whether the lack of successful treatment with first-line therapy with an IL-17A inhibitor was primary (no response at all) or secondary (initial response and later failure). One presumes that patients with primary failures are less likely to respond to another IL-17A inhibitor compared with patients with secondary failures. Nevertheless, this large population-based study suggests that the failure of first-line IL-17A inhibitor therapy should not deter treatment with second-line IL-17A inhibitors.

Finally, Schett and colleagues looked at serum cytokine changes after treatment with guselkumab in patients with PsA with inadequate response to TNF inhibitor (TNFI-IR). Using clinical data and biosamples from patients enrolled in the COSMOS study, which included patients with active PsA and TNFI-IR who were randomly assigned to receive either guselkumab (n = 189) or placebo (n = 96), they showed that the serum levels of IL-17A, IL-17F, IL-22, and serum amyloid A were reduced significantly by week 4 and were sustained through week 48 in the guselkumab group vs the placebo group. Patients who achieved a clinical response to guselkumab at week 24 showed higher baseline IL-22 and interferon-γ levels as well as a significant reduction in IL-6 levels at week 4 compared with nonresponders. These markers are candidates for predictors for response to guselkumab in this population.

To address this gap in knowledge, Möller and colleagues compared the effectiveness of the first bDMARD in patients with PsA with low vs high joint counts (LJC and HJC, respectively). Using the Swiss Clinical Quality Management registry for rheumatic diseases, they obtained data on 387 patients with PsA who had either LJC (n = 197) or HJC (n = 190) and received bDMARD. As expected, patients with HJC had a higher burden of disease. Despite the higher burden, patients in both groups showed similar treatment efficacy in terms of drug retention. Consistent with previous reports, female sex was associated with lower treatment persistence, whereas concomitant treatment with conventional synthetic DMARD (csDMARD) was associated with longer bDMARD persistence. Thus, baseline joint counts may not be a good criterion for choosing who should be treated with bDMARD. The presence of active disease and lack of response to prior csDMARD is sufficient.

Persistence with therapy is an important indicator of drug effectiveness in the real world. A recent report from the CorEvitas registry by Mease and colleagues demonstrated that nearly 80% of patients with PsA persisted with guselkumab (an interleukin [IL]–23 inhibitor) treatment for 6 months and showed improvements in peripheral joint and skin symptoms. This study evaluated 114 patients with active PsA,  > 90% of whom were previously treated with b- and tsDMARD. The mean scores for clinical Disease Activity Index in PsA, overall joint and skin activity, patient-reported pain, and body surface area with psoriasis improved significantly.

Choosing the next therapy after lack of success with treatment with a tumour necrosis factor (TNF) inhibitor and an IL-17A inhibitor is difficult. One question is whether one should try another IL-17A inhibitor or move to another class of therapy. Hansen and colleagues tried to address this question by analyses of data from the Danish Rheumatology Registry. Patients with PsA who underwent prior treatment with one or more TNF inhibitor and switched to either first-line (n = 534) or second-line (n = 102) IL-17A inhibitors (ixekizumab or secukinumab) were included. Similar persistence with therapy was observed between first-line and second-line IL-17A inhibitor switchers and between second-line secukinumab and second-line ixekizumab switchers. Withdrawal reasons were similar for both first-line and second-line switchers when considering adverse events; however, withdrawal due to lack of successful therapy was higher for the first-line vs second-line switchers (34% vs 18%). An important piece of information missing in the report was whether the lack of successful treatment with first-line therapy with an IL-17A inhibitor was primary (no response at all) or secondary (initial response and later failure). One presumes that patients with primary failures are less likely to respond to another IL-17A inhibitor compared with patients with secondary failures. Nevertheless, this large population-based study suggests that the failure of first-line IL-17A inhibitor therapy should not deter treatment with second-line IL-17A inhibitors.

Finally, Schett and colleagues looked at serum cytokine changes after treatment with guselkumab in patients with PsA with inadequate response to TNF inhibitor (TNFI-IR). Using clinical data and biosamples from patients enrolled in the COSMOS study, which included patients with active PsA and TNFI-IR who were randomly assigned to receive either guselkumab (n = 189) or placebo (n = 96), they showed that the serum levels of IL-17A, IL-17F, IL-22, and serum amyloid A were reduced significantly by week 4 and were sustained through week 48 in the guselkumab group vs the placebo group. Patients who achieved a clinical response to guselkumab at week 24 showed higher baseline IL-22 and interferon-γ levels as well as a significant reduction in IL-6 levels at week 4 compared with nonresponders. These markers are candidates for predictors for response to guselkumab in this population.

To address this gap in knowledge, Möller and colleagues compared the effectiveness of the first bDMARD in patients with PsA with low vs high joint counts (LJC and HJC, respectively). Using the Swiss Clinical Quality Management registry for rheumatic diseases, they obtained data on 387 patients with PsA who had either LJC (n = 197) or HJC (n = 190) and received bDMARD. As expected, patients with HJC had a higher burden of disease. Despite the higher burden, patients in both groups showed similar treatment efficacy in terms of drug retention. Consistent with previous reports, female sex was associated with lower treatment persistence, whereas concomitant treatment with conventional synthetic DMARD (csDMARD) was associated with longer bDMARD persistence. Thus, baseline joint counts may not be a good criterion for choosing who should be treated with bDMARD. The presence of active disease and lack of response to prior csDMARD is sufficient.

Persistence with therapy is an important indicator of drug effectiveness in the real world. A recent report from the CorEvitas registry by Mease and colleagues demonstrated that nearly 80% of patients with PsA persisted with guselkumab (an interleukin [IL]–23 inhibitor) treatment for 6 months and showed improvements in peripheral joint and skin symptoms. This study evaluated 114 patients with active PsA,  > 90% of whom were previously treated with b- and tsDMARD. The mean scores for clinical Disease Activity Index in PsA, overall joint and skin activity, patient-reported pain, and body surface area with psoriasis improved significantly.

Choosing the next therapy after lack of success with treatment with a tumour necrosis factor (TNF) inhibitor and an IL-17A inhibitor is difficult. One question is whether one should try another IL-17A inhibitor or move to another class of therapy. Hansen and colleagues tried to address this question by analyses of data from the Danish Rheumatology Registry. Patients with PsA who underwent prior treatment with one or more TNF inhibitor and switched to either first-line (n = 534) or second-line (n = 102) IL-17A inhibitors (ixekizumab or secukinumab) were included. Similar persistence with therapy was observed between first-line and second-line IL-17A inhibitor switchers and between second-line secukinumab and second-line ixekizumab switchers. Withdrawal reasons were similar for both first-line and second-line switchers when considering adverse events; however, withdrawal due to lack of successful therapy was higher for the first-line vs second-line switchers (34% vs 18%). An important piece of information missing in the report was whether the lack of successful treatment with first-line therapy with an IL-17A inhibitor was primary (no response at all) or secondary (initial response and later failure). One presumes that patients with primary failures are less likely to respond to another IL-17A inhibitor compared with patients with secondary failures. Nevertheless, this large population-based study suggests that the failure of first-line IL-17A inhibitor therapy should not deter treatment with second-line IL-17A inhibitors.

Finally, Schett and colleagues looked at serum cytokine changes after treatment with guselkumab in patients with PsA with inadequate response to TNF inhibitor (TNFI-IR). Using clinical data and biosamples from patients enrolled in the COSMOS study, which included patients with active PsA and TNFI-IR who were randomly assigned to receive either guselkumab (n = 189) or placebo (n = 96), they showed that the serum levels of IL-17A, IL-17F, IL-22, and serum amyloid A were reduced significantly by week 4 and were sustained through week 48 in the guselkumab group vs the placebo group. Patients who achieved a clinical response to guselkumab at week 24 showed higher baseline IL-22 and interferon-γ levels as well as a significant reduction in IL-6 levels at week 4 compared with nonresponders. These markers are candidates for predictors for response to guselkumab in this population.

Key clinical point: Fremanezumab was effective as a preventive treatment in patients with chronic migraine (CM) with or without medication overuse (MO) and showed potential benefits in reducing MO.

Major finding: During a 12-week follow-up period, the administration of monthly and quarterly fremanezumab vs placebo led to significantly reduced average number of monthly headache days of moderate or greater severity in patients with MO (monthly: mean change [∆] −2.0, P = .0012; and quarterly: ∆ −1.8, P = .0042) and without MO (monthly: ∆ −1.6, P = .0437; and quarterly: ∆ −1.5, P = .0441). A greater proportion of patients receiving fremanezumab vs placebo reverted to no MO (P ≤ .05).

Study details: This post hoc analysis of a phase 2b/3 trial included 479 Japanese patients with CM who were randomly assigned to receive monthly fremanezumab (n = 159), quarterly fremanezumab (n = 159), or placebo (n = 161), and of whom 320 patients reported MO.

Disclosures: This study was funded by Otsuka Pharmaceutical Co., Ltd. Several authors declared being full-time employees of Otsuka Pharmaceutical Co., Ltd., and N Imai declared ties with various other sources.

Source: Imai N et al. Effects of fremanezumab on medication overuse in Japanese chronic migraine patients: Post hoc analysis of a multicenter, randomized, double-blind, placebo-controlled trial. Neurol Ther. 2023 (Sep 11). doi: 10.1007/s40120-023-00531-3

Key clinical point: Fremanezumab was effective as a preventive treatment in patients with chronic migraine (CM) with or without medication overuse (MO) and showed potential benefits in reducing MO.

Major finding: During a 12-week follow-up period, the administration of monthly and quarterly fremanezumab vs placebo led to significantly reduced average number of monthly headache days of moderate or greater severity in patients with MO (monthly: mean change [∆] −2.0, P = .0012; and quarterly: ∆ −1.8, P = .0042) and without MO (monthly: ∆ −1.6, P = .0437; and quarterly: ∆ −1.5, P = .0441). A greater proportion of patients receiving fremanezumab vs placebo reverted to no MO (P ≤ .05).

Study details: This post hoc analysis of a phase 2b/3 trial included 479 Japanese patients with CM who were randomly assigned to receive monthly fremanezumab (n = 159), quarterly fremanezumab (n = 159), or placebo (n = 161), and of whom 320 patients reported MO.

Disclosures: This study was funded by Otsuka Pharmaceutical Co., Ltd. Several authors declared being full-time employees of Otsuka Pharmaceutical Co., Ltd., and N Imai declared ties with various other sources.

Source: Imai N et al. Effects of fremanezumab on medication overuse in Japanese chronic migraine patients: Post hoc analysis of a multicenter, randomized, double-blind, placebo-controlled trial. Neurol Ther. 2023 (Sep 11). doi: 10.1007/s40120-023-00531-3

Key clinical point: Fremanezumab was effective as a preventive treatment in patients with chronic migraine (CM) with or without medication overuse (MO) and showed potential benefits in reducing MO.

Major finding: During a 12-week follow-up period, the administration of monthly and quarterly fremanezumab vs placebo led to significantly reduced average number of monthly headache days of moderate or greater severity in patients with MO (monthly: mean change [∆] −2.0, P = .0012; and quarterly: ∆ −1.8, P = .0042) and without MO (monthly: ∆ −1.6, P = .0437; and quarterly: ∆ −1.5, P = .0441). A greater proportion of patients receiving fremanezumab vs placebo reverted to no MO (P ≤ .05).

Study details: This post hoc analysis of a phase 2b/3 trial included 479 Japanese patients with CM who were randomly assigned to receive monthly fremanezumab (n = 159), quarterly fremanezumab (n = 159), or placebo (n = 161), and of whom 320 patients reported MO.

Disclosures: This study was funded by Otsuka Pharmaceutical Co., Ltd. Several authors declared being full-time employees of Otsuka Pharmaceutical Co., Ltd., and N Imai declared ties with various other sources.

Source: Imai N et al. Effects of fremanezumab on medication overuse in Japanese chronic migraine patients: Post hoc analysis of a multicenter, randomized, double-blind, placebo-controlled trial. Neurol Ther. 2023 (Sep 11). doi: 10.1007/s40120-023-00531-3

Key clinical point: Patients with migraine who achieved ≥ 50% reduction in headache days at 6 months (responders) with anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAb) showed an even greater reduction in the number of days per month with photophobia, phonophobia, and aura ratios.

Major finding: Monthly headache days reduced significantly by 9.4 days/month (P < .001) and 2.2 days/month (P = .004) among responders and non-responders, respectively, with responders having additional significant reductions in photophobia (−19.5%; P < .001), phonophobia (−12.1%; P = .010), and aura (−25.1%; P = .008) ratios. Higher basal photophobia ratios were predictors of increased response rates between months 3 and 6 (incidence risk ratio 0.928; P = .040).

Study details: This prospective observational study included 158 patients with migraine treated with anti-CGRP mAb, of whom 43.7% were responders.

Disclosures: This study did not receive any funding. A Alpuente, E Caronna, M Torres-Ferrús, and P Pozo-Rosich declared receiving honoraria as consultants or speakers from various sources.

Source: Alpuente A et al. Impact of anti-CGRP monoclonal antibodies on migraine attack accompanying symptoms: A real-world evidence study. Cephalalgia. 2023;43(8):3331024231177636 (Aug 9). doi: 10.1177/03331024231177636

Key clinical point: Patients with migraine who achieved ≥ 50% reduction in headache days at 6 months (responders) with anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAb) showed an even greater reduction in the number of days per month with photophobia, phonophobia, and aura ratios.

Major finding: Monthly headache days reduced significantly by 9.4 days/month (P < .001) and 2.2 days/month (P = .004) among responders and non-responders, respectively, with responders having additional significant reductions in photophobia (−19.5%; P < .001), phonophobia (−12.1%; P = .010), and aura (−25.1%; P = .008) ratios. Higher basal photophobia ratios were predictors of increased response rates between months 3 and 6 (incidence risk ratio 0.928; P = .040).

Study details: This prospective observational study included 158 patients with migraine treated with anti-CGRP mAb, of whom 43.7% were responders.

Disclosures: This study did not receive any funding. A Alpuente, E Caronna, M Torres-Ferrús, and P Pozo-Rosich declared receiving honoraria as consultants or speakers from various sources.

Source: Alpuente A et al. Impact of anti-CGRP monoclonal antibodies on migraine attack accompanying symptoms: A real-world evidence study. Cephalalgia. 2023;43(8):3331024231177636 (Aug 9). doi: 10.1177/03331024231177636

Key clinical point: Patients with migraine who achieved ≥ 50% reduction in headache days at 6 months (responders) with anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAb) showed an even greater reduction in the number of days per month with photophobia, phonophobia, and aura ratios.

Major finding: Monthly headache days reduced significantly by 9.4 days/month (P < .001) and 2.2 days/month (P = .004) among responders and non-responders, respectively, with responders having additional significant reductions in photophobia (−19.5%; P < .001), phonophobia (−12.1%; P = .010), and aura (−25.1%; P = .008) ratios. Higher basal photophobia ratios were predictors of increased response rates between months 3 and 6 (incidence risk ratio 0.928; P = .040).

Study details: This prospective observational study included 158 patients with migraine treated with anti-CGRP mAb, of whom 43.7% were responders.

Disclosures: This study did not receive any funding. A Alpuente, E Caronna, M Torres-Ferrús, and P Pozo-Rosich declared receiving honoraria as consultants or speakers from various sources.

Source: Alpuente A et al. Impact of anti-CGRP monoclonal antibodies on migraine attack accompanying symptoms: A real-world evidence study. Cephalalgia. 2023;43(8):3331024231177636 (Aug 9). doi: 10.1177/03331024231177636

Key clinical point: No appreciable association was observed between a history of migraine or its subtypes and an increase in the risk for COVID-19, including hospitalization for COVID-19, in older women.

Major finding: No significant association was observed between a history of migraine and the risk of developing COVID-19 (odds ratio [OR] 1.08; 95% CI 0.95-1.22) or being hospitalized for COVID-19 (OR 1.20; 95% CI 0.86-1.68) among older women. Similarly, other migraine statuses, including migraine with aura, showed no association with the risk for COVID-19.

Study details: This prospective cohort study included 16,492 women (age ≥ 45 years) enrolled in the Women’s Health Study, of whom 28.9% had a history of migraine and 7.7% reported positive SARS-CoV-2 test results, a diagnosis of COVID-19, or hospitalization for COVID-19.

Disclosures: The Women’s Health Study was funded by grants from the US National Cancer Institute and the US National Heart, Lung, and Blood Institute. T Kurth declared receiving research grants and personal compensation from various sources. The other authors declared no conflicts of interest.

Source: Rist PM et al. History of migraine and risk of COVID-19: A cohort study. Am J Med. 2023 (Aug 18). doi: 10.1016/j.amjmed.2023.07.021

Key clinical point: No appreciable association was observed between a history of migraine or its subtypes and an increase in the risk for COVID-19, including hospitalization for COVID-19, in older women.

Major finding: No significant association was observed between a history of migraine and the risk of developing COVID-19 (odds ratio [OR] 1.08; 95% CI 0.95-1.22) or being hospitalized for COVID-19 (OR 1.20; 95% CI 0.86-1.68) among older women. Similarly, other migraine statuses, including migraine with aura, showed no association with the risk for COVID-19.

Study details: This prospective cohort study included 16,492 women (age ≥ 45 years) enrolled in the Women’s Health Study, of whom 28.9% had a history of migraine and 7.7% reported positive SARS-CoV-2 test results, a diagnosis of COVID-19, or hospitalization for COVID-19.

Disclosures: The Women’s Health Study was funded by grants from the US National Cancer Institute and the US National Heart, Lung, and Blood Institute. T Kurth declared receiving research grants and personal compensation from various sources. The other authors declared no conflicts of interest.

Source: Rist PM et al. History of migraine and risk of COVID-19: A cohort study. Am J Med. 2023 (Aug 18). doi: 10.1016/j.amjmed.2023.07.021

Key clinical point: No appreciable association was observed between a history of migraine or its subtypes and an increase in the risk for COVID-19, including hospitalization for COVID-19, in older women.

Major finding: No significant association was observed between a history of migraine and the risk of developing COVID-19 (odds ratio [OR] 1.08; 95% CI 0.95-1.22) or being hospitalized for COVID-19 (OR 1.20; 95% CI 0.86-1.68) among older women. Similarly, other migraine statuses, including migraine with aura, showed no association with the risk for COVID-19.

Study details: This prospective cohort study included 16,492 women (age ≥ 45 years) enrolled in the Women’s Health Study, of whom 28.9% had a history of migraine and 7.7% reported positive SARS-CoV-2 test results, a diagnosis of COVID-19, or hospitalization for COVID-19.

Disclosures: The Women’s Health Study was funded by grants from the US National Cancer Institute and the US National Heart, Lung, and Blood Institute. T Kurth declared receiving research grants and personal compensation from various sources. The other authors declared no conflicts of interest.

Source: Rist PM et al. History of migraine and risk of COVID-19: A cohort study. Am J Med. 2023 (Aug 18). doi: 10.1016/j.amjmed.2023.07.021

Key clinical point: Nearly 24% of patients with multiple sclerosis (MS) experience migraine, with the odds of migraine occurrence being approximately 2-fold higher in patients with MS compared with control individuals.

Major finding: The overall prevalence rate of migraine among patients with MS was 0.24 (95% CI 0.21-0.28). Moreover, patients with MS vs control participants without MS had a ~2-fold greater risk of experiencing migraine (odds ratio 1.96; 95% CI 1.20-3.20).

Study details: This meta-analysis of 35 studies included 279,620 patients with MS and 279,603 control participants without MS.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Mohammadi M et al. The association between multiple sclerosis and migraine: A meta-analysis. Mult Scler Relat Disord. 2023;79:104954 (Aug 30). doi: 10.1016/j.msard.2023.104954

Key clinical point: Nearly 24% of patients with multiple sclerosis (MS) experience migraine, with the odds of migraine occurrence being approximately 2-fold higher in patients with MS compared with control individuals.

Major finding: The overall prevalence rate of migraine among patients with MS was 0.24 (95% CI 0.21-0.28). Moreover, patients with MS vs control participants without MS had a ~2-fold greater risk of experiencing migraine (odds ratio 1.96; 95% CI 1.20-3.20).

Study details: This meta-analysis of 35 studies included 279,620 patients with MS and 279,603 control participants without MS.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Mohammadi M et al. The association between multiple sclerosis and migraine: A meta-analysis. Mult Scler Relat Disord. 2023;79:104954 (Aug 30). doi: 10.1016/j.msard.2023.104954

Key clinical point: Nearly 24% of patients with multiple sclerosis (MS) experience migraine, with the odds of migraine occurrence being approximately 2-fold higher in patients with MS compared with control individuals.

Major finding: The overall prevalence rate of migraine among patients with MS was 0.24 (95% CI 0.21-0.28). Moreover, patients with MS vs control participants without MS had a ~2-fold greater risk of experiencing migraine (odds ratio 1.96; 95% CI 1.20-3.20).

Study details: This meta-analysis of 35 studies included 279,620 patients with MS and 279,603 control participants without MS.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Mohammadi M et al. The association between multiple sclerosis and migraine: A meta-analysis. Mult Scler Relat Disord. 2023;79:104954 (Aug 30). doi: 10.1016/j.msard.2023.104954

Key clinical point: Absence of cutaneous allodynia was a predictor of treatment response following withdrawal therapy in patients with chronic migraine and medication overuse, with the predictive value being even more pronounced when compared with cephalic or extracephalic allodynia.

Major finding: The chances of reversion from chronic to episodic migraine were ~2.5 times higher in patients without vs with cutaneous allodynia (odds ratio [OR] 2.45; P = .042), with the predictive values of absence of allodynia being even more pronounced when compared with patients having cephalic (OR 4.16; P = .024) or extracephalic (OR 7.32; P = .003) allodynia.

Study details: This study, conducted as part of the Chronification And Reversibility of Migraine study, included 173 patients with chronic migraine and medication overuse, of whom 129 had cutaneous allodynia.

Disclosures: This study was supported by grants from the Netherlands Organization for Scientific Research and the Dutch Brain Foundation. I de Boer and GM Terwindt declared receiving independent support, consultancy support, or both from various sources.

Source: Pijpers JA et al. Cutaneous allodynia as predictor for treatment response in chronic migraine: A cohort study. J Headache Pain. 2023;24:118 (Aug 30). Doi: 10.1186/s10194-023-01651-9.

Key clinical point: Absence of cutaneous allodynia was a predictor of treatment response following withdrawal therapy in patients with chronic migraine and medication overuse, with the predictive value being even more pronounced when compared with cephalic or extracephalic allodynia.

Major finding: The chances of reversion from chronic to episodic migraine were ~2.5 times higher in patients without vs with cutaneous allodynia (odds ratio [OR] 2.45; P = .042), with the predictive values of absence of allodynia being even more pronounced when compared with patients having cephalic (OR 4.16; P = .024) or extracephalic (OR 7.32; P = .003) allodynia.

Study details: This study, conducted as part of the Chronification And Reversibility of Migraine study, included 173 patients with chronic migraine and medication overuse, of whom 129 had cutaneous allodynia.

Disclosures: This study was supported by grants from the Netherlands Organization for Scientific Research and the Dutch Brain Foundation. I de Boer and GM Terwindt declared receiving independent support, consultancy support, or both from various sources.

Source: Pijpers JA et al. Cutaneous allodynia as predictor for treatment response in chronic migraine: A cohort study. J Headache Pain. 2023;24:118 (Aug 30). Doi: 10.1186/s10194-023-01651-9.

Key clinical point: Absence of cutaneous allodynia was a predictor of treatment response following withdrawal therapy in patients with chronic migraine and medication overuse, with the predictive value being even more pronounced when compared with cephalic or extracephalic allodynia.

Major finding: The chances of reversion from chronic to episodic migraine were ~2.5 times higher in patients without vs with cutaneous allodynia (odds ratio [OR] 2.45; P = .042), with the predictive values of absence of allodynia being even more pronounced when compared with patients having cephalic (OR 4.16; P = .024) or extracephalic (OR 7.32; P = .003) allodynia.

Study details: This study, conducted as part of the Chronification And Reversibility of Migraine study, included 173 patients with chronic migraine and medication overuse, of whom 129 had cutaneous allodynia.

Disclosures: This study was supported by grants from the Netherlands Organization for Scientific Research and the Dutch Brain Foundation. I de Boer and GM Terwindt declared receiving independent support, consultancy support, or both from various sources.

Source: Pijpers JA et al. Cutaneous allodynia as predictor for treatment response in chronic migraine: A cohort study. J Headache Pain. 2023;24:118 (Aug 30). Doi: 10.1186/s10194-023-01651-9.