Clinical Edge Journal Scan

Key clinical point: Repetitive intravenous dihydroergotamine (DHE) administration using an inpatient protocol seemed effective and tolerable in patients with refractory chronic migraine (rCM), even in those at an elevated risk for atherosclerotic cardiovascular disease (ASCVD).

Major finding: The elevated-ASCVD vs low-ASCVD risk group had fewer patients receiving the maximum dose of DHE (42.2% vs 64.4%; P = .002) and lower median doses of DHE on discharge (0.75 vs 1.00 mg; P < .001). Both groups experienced significant pain reduction, but it was more pronounced in the low-ASCVD risk group (P = .037). No significant cardiovascular adverse events or electrocardiogram abnormalities were reported in either group.

Study details: This single-center retrospective cohort study included 347 patients with rCM who received inpatient intravenous DHE, of whom 64 and 163 patients had elevated and low ASCVD risk, respectively.

Disclosures: This study was partially funded by Impel Pharmaceuticals, Inc. Two authors declared being full-time employees and stockowners of Impel Pharmaceuticals. Some authors declared ties with various sources, including Impel Pharmaceuticals.

Source: Wang VS et al. Safety, tolerability, and effectiveness of repetitive intravenous dihydroergotamine for refractory chronic migraine with cardiovascular risk factors: A retrospective study. Headache. 2023;63(9):1251-1258 (Sep 23). doi: 10.1111/head.14636

Key clinical point: Repetitive intravenous dihydroergotamine (DHE) administration using an inpatient protocol seemed effective and tolerable in patients with refractory chronic migraine (rCM), even in those at an elevated risk for atherosclerotic cardiovascular disease (ASCVD).

Major finding: The elevated-ASCVD vs low-ASCVD risk group had fewer patients receiving the maximum dose of DHE (42.2% vs 64.4%; P = .002) and lower median doses of DHE on discharge (0.75 vs 1.00 mg; P < .001). Both groups experienced significant pain reduction, but it was more pronounced in the low-ASCVD risk group (P = .037). No significant cardiovascular adverse events or electrocardiogram abnormalities were reported in either group.

Study details: This single-center retrospective cohort study included 347 patients with rCM who received inpatient intravenous DHE, of whom 64 and 163 patients had elevated and low ASCVD risk, respectively.

Disclosures: This study was partially funded by Impel Pharmaceuticals, Inc. Two authors declared being full-time employees and stockowners of Impel Pharmaceuticals. Some authors declared ties with various sources, including Impel Pharmaceuticals.

Source: Wang VS et al. Safety, tolerability, and effectiveness of repetitive intravenous dihydroergotamine for refractory chronic migraine with cardiovascular risk factors: A retrospective study. Headache. 2023;63(9):1251-1258 (Sep 23). doi: 10.1111/head.14636

Key clinical point: Repetitive intravenous dihydroergotamine (DHE) administration using an inpatient protocol seemed effective and tolerable in patients with refractory chronic migraine (rCM), even in those at an elevated risk for atherosclerotic cardiovascular disease (ASCVD).

Major finding: The elevated-ASCVD vs low-ASCVD risk group had fewer patients receiving the maximum dose of DHE (42.2% vs 64.4%; P = .002) and lower median doses of DHE on discharge (0.75 vs 1.00 mg; P < .001). Both groups experienced significant pain reduction, but it was more pronounced in the low-ASCVD risk group (P = .037). No significant cardiovascular adverse events or electrocardiogram abnormalities were reported in either group.

Study details: This single-center retrospective cohort study included 347 patients with rCM who received inpatient intravenous DHE, of whom 64 and 163 patients had elevated and low ASCVD risk, respectively.

Disclosures: This study was partially funded by Impel Pharmaceuticals, Inc. Two authors declared being full-time employees and stockowners of Impel Pharmaceuticals. Some authors declared ties with various sources, including Impel Pharmaceuticals.

Source: Wang VS et al. Safety, tolerability, and effectiveness of repetitive intravenous dihydroergotamine for refractory chronic migraine with cardiovascular risk factors: A retrospective study. Headache. 2023;63(9):1251-1258 (Sep 23). doi: 10.1111/head.14636

The ZUMA-7 and TRANSFORM studies have been practice-changing for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). These studies demonstrated an improvement in outcomes with axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), respectively, as compared with standard-of-care treatment (chemotherapy and autologous stem cell transplantation).^1,2 Patients included in these studies were refractory to their initial therapy or experienced relapse within 12 months and were considered fit for autologous stem cell transplant. It has remained unclear, however, whether patients who are not transplant candidates may also derive benefit and tolerate treatment with chimeric antigen receptor (CAR) T-cell therapy. The PILOT study was a single-arm phase 2 study that demonstrated favorable outcomes with liso-cel in this patient population, thus resulting in the approval of liso-cel by the US Food and Drug Administration for this population.³ Recently, the ALYCATE study similarly examined outcomes in transplant-ineligible patients treated with axi-cel (Houot et al). This phase 2 study included 62 patients with high-risk R/R LBCL who underwent leukapheresis and subsequently received second-line axi-cel. The complete metabolic response rate 3 months after axi-cel infusion was 71.0% (95% CI 58.1%-81.8%). At a median 12-month follow-up, the median progression-free survival was 11.8 months (95% CI 8.4-not reached) whereas median overall survival was not reached. Grade ≥ 3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 8.1% and 14.5% of patients, respectively. Also of note, patients age ≥ 70 years did not show increased toxicity compared with those age < 70 years, with similar rates of CRS, ICANS, and intensive care unit transfer. This study supports the role of axi-cel in the second-line setting, regardless of transplant eligibility.

Another important study recently published for patients with LBCL examined the role of central nervous system (CNS) prophylaxis (Lewis et al). We know that certain patients with LBCL, including those with a high CNS international prognostic index (IPI) score, double-hit lymphoma, or disease involvement of multiple or certain extranodal sites (ie, breast, testes, adrenals, kidney) can be at increased risk for lymphoma spread to the CNS.⁴ Strategies to reduce this risk have subsequently been developed for these high-risk patients, though consensus regarding who should be treated and how best to treat patients has been consistent. Recently, retrospective data have also called into question whether our current approaches meaningfully reduce this risk. One such study was a multicenter, international, retrospective observational study that included 2418 adults with aggressive LBCL and a high risk for CNS progression who were treated with curative-intent anti-CD20–based chemoimmunotherapy and who did or did not receive high-dose methotrexate (HD-MTX). Patients who did vs did not receive HD-MTX had a significantly lower risk for CNS progression (adjusted 5-year risk difference 1.6%; adjusted hazard ratio [aHR] 0.59; P = .014), but the significance was lost when considering only those patients who achieved a complete response at chemoimmunotherapy completion (adjusted 5-year risk difference 1.4%; aHR 0.74; P = .30). The study was not sufficiently powered to make definitive conclusions for individual risk groups, though there was no obvious reduction in CNS involvement risk in any high-risk subgroup. With an absolute risk reduction of 1.6% with the use of HD-MTX, 63 patients would require treatment to prevent one CNS progression event over 5 years (Lewis et al). Given the absence of prospective, randomized data, these results, though retrospective in nature, call into question the benefit of CNS prophylaxis. The authors suggest that studies evaluating alternative strategies for prophylaxis and tools for early detection of relapse, such as circulating tumor DNA, may be helpful.

Another study worth noting was one exploring Bruton tyrosine kinase (BTK) inhibition in mantle cell lymphoma (MCL). BTK inhibitors, including zanubrutinib, have emerged as effective therapies for patients with R/R disease. A recent pooled analysis included 112 patients from the BGB-3111-AU-003 and BGB-3111-206 clinical trials who had R/R MCL and received second-line (n = 41) or later-line (n = 71) zanubrutinib (Song et al). At a median follow-up of 35.2 months, patients receiving second-line vs later-line zanubrutinib had significantly improved median overall survival (aHR 0.459; P = .044) and numerically longer median progression-free survival (27.8 vs 22.1 months). Adverse events observed in both groups were consistent with the known safety profile of zanubrutinib. These findings were in line with a prior similar pooled study that demonstrated improved outcomes with second-line ibrutinib for patients with MCL as compared with later-line ibrutinib therapy.⁵ This study, however, did not evaluate the impact on CAR T–cell therapy in MCL, which is also an effective treatment option for patients with R/R disease, and how best to sequence with BTK inhibitors.

Additional References

1.       Locke FL, Miklos DB, Jacobson CA, et al, for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133

2.       Kamdar M, Solomon SR, Arnason J, et al, for theTRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. doi: 10.1016/S0140-6736(22)00662-6

3.       Gordon LI, Liu FF, Braverman J, et al. Lisocabtagene maraleucel for second-line relapsed or refractory large B-cell lymphoma: Patient-reported outcomes from the PILOT study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283162

4.       Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34:3150-3156. doi: 10.1200/JCO.2015.65.6520

5.       Dreyling M, Goy A, Hess G, et al. Long-term outcomes with ibrutinib treatment for patients with relapsed/refractory mantle cell lymphoma: A pooled analysis of 3 clinical trials with nearly 10 years of follow-up. Hemasphere. 2022;6:e712. doi: 10.1097/HS9.0000000000000712

The ZUMA-7 and TRANSFORM studies have been practice-changing for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). These studies demonstrated an improvement in outcomes with axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), respectively, as compared with standard-of-care treatment (chemotherapy and autologous stem cell transplantation).^1,2 Patients included in these studies were refractory to their initial therapy or experienced relapse within 12 months and were considered fit for autologous stem cell transplant. It has remained unclear, however, whether patients who are not transplant candidates may also derive benefit and tolerate treatment with chimeric antigen receptor (CAR) T-cell therapy. The PILOT study was a single-arm phase 2 study that demonstrated favorable outcomes with liso-cel in this patient population, thus resulting in the approval of liso-cel by the US Food and Drug Administration for this population.³ Recently, the ALYCATE study similarly examined outcomes in transplant-ineligible patients treated with axi-cel (Houot et al). This phase 2 study included 62 patients with high-risk R/R LBCL who underwent leukapheresis and subsequently received second-line axi-cel. The complete metabolic response rate 3 months after axi-cel infusion was 71.0% (95% CI 58.1%-81.8%). At a median 12-month follow-up, the median progression-free survival was 11.8 months (95% CI 8.4-not reached) whereas median overall survival was not reached. Grade ≥ 3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 8.1% and 14.5% of patients, respectively. Also of note, patients age ≥ 70 years did not show increased toxicity compared with those age < 70 years, with similar rates of CRS, ICANS, and intensive care unit transfer. This study supports the role of axi-cel in the second-line setting, regardless of transplant eligibility.

Another important study recently published for patients with LBCL examined the role of central nervous system (CNS) prophylaxis (Lewis et al). We know that certain patients with LBCL, including those with a high CNS international prognostic index (IPI) score, double-hit lymphoma, or disease involvement of multiple or certain extranodal sites (ie, breast, testes, adrenals, kidney) can be at increased risk for lymphoma spread to the CNS.⁴ Strategies to reduce this risk have subsequently been developed for these high-risk patients, though consensus regarding who should be treated and how best to treat patients has been consistent. Recently, retrospective data have also called into question whether our current approaches meaningfully reduce this risk. One such study was a multicenter, international, retrospective observational study that included 2418 adults with aggressive LBCL and a high risk for CNS progression who were treated with curative-intent anti-CD20–based chemoimmunotherapy and who did or did not receive high-dose methotrexate (HD-MTX). Patients who did vs did not receive HD-MTX had a significantly lower risk for CNS progression (adjusted 5-year risk difference 1.6%; adjusted hazard ratio [aHR] 0.59; P = .014), but the significance was lost when considering only those patients who achieved a complete response at chemoimmunotherapy completion (adjusted 5-year risk difference 1.4%; aHR 0.74; P = .30). The study was not sufficiently powered to make definitive conclusions for individual risk groups, though there was no obvious reduction in CNS involvement risk in any high-risk subgroup. With an absolute risk reduction of 1.6% with the use of HD-MTX, 63 patients would require treatment to prevent one CNS progression event over 5 years (Lewis et al). Given the absence of prospective, randomized data, these results, though retrospective in nature, call into question the benefit of CNS prophylaxis. The authors suggest that studies evaluating alternative strategies for prophylaxis and tools for early detection of relapse, such as circulating tumor DNA, may be helpful.

Another study worth noting was one exploring Bruton tyrosine kinase (BTK) inhibition in mantle cell lymphoma (MCL). BTK inhibitors, including zanubrutinib, have emerged as effective therapies for patients with R/R disease. A recent pooled analysis included 112 patients from the BGB-3111-AU-003 and BGB-3111-206 clinical trials who had R/R MCL and received second-line (n = 41) or later-line (n = 71) zanubrutinib (Song et al). At a median follow-up of 35.2 months, patients receiving second-line vs later-line zanubrutinib had significantly improved median overall survival (aHR 0.459; P = .044) and numerically longer median progression-free survival (27.8 vs 22.1 months). Adverse events observed in both groups were consistent with the known safety profile of zanubrutinib. These findings were in line with a prior similar pooled study that demonstrated improved outcomes with second-line ibrutinib for patients with MCL as compared with later-line ibrutinib therapy.⁵ This study, however, did not evaluate the impact on CAR T–cell therapy in MCL, which is also an effective treatment option for patients with R/R disease, and how best to sequence with BTK inhibitors.

Additional References

1.       Locke FL, Miklos DB, Jacobson CA, et al, for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133

2.       Kamdar M, Solomon SR, Arnason J, et al, for theTRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. doi: 10.1016/S0140-6736(22)00662-6

3.       Gordon LI, Liu FF, Braverman J, et al. Lisocabtagene maraleucel for second-line relapsed or refractory large B-cell lymphoma: Patient-reported outcomes from the PILOT study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283162

4.       Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34:3150-3156. doi: 10.1200/JCO.2015.65.6520

5.       Dreyling M, Goy A, Hess G, et al. Long-term outcomes with ibrutinib treatment for patients with relapsed/refractory mantle cell lymphoma: A pooled analysis of 3 clinical trials with nearly 10 years of follow-up. Hemasphere. 2022;6:e712. doi: 10.1097/HS9.0000000000000712

The ZUMA-7 and TRANSFORM studies have been practice-changing for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). These studies demonstrated an improvement in outcomes with axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), respectively, as compared with standard-of-care treatment (chemotherapy and autologous stem cell transplantation).^1,2 Patients included in these studies were refractory to their initial therapy or experienced relapse within 12 months and were considered fit for autologous stem cell transplant. It has remained unclear, however, whether patients who are not transplant candidates may also derive benefit and tolerate treatment with chimeric antigen receptor (CAR) T-cell therapy. The PILOT study was a single-arm phase 2 study that demonstrated favorable outcomes with liso-cel in this patient population, thus resulting in the approval of liso-cel by the US Food and Drug Administration for this population.³ Recently, the ALYCATE study similarly examined outcomes in transplant-ineligible patients treated with axi-cel (Houot et al). This phase 2 study included 62 patients with high-risk R/R LBCL who underwent leukapheresis and subsequently received second-line axi-cel. The complete metabolic response rate 3 months after axi-cel infusion was 71.0% (95% CI 58.1%-81.8%). At a median 12-month follow-up, the median progression-free survival was 11.8 months (95% CI 8.4-not reached) whereas median overall survival was not reached. Grade ≥ 3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 8.1% and 14.5% of patients, respectively. Also of note, patients age ≥ 70 years did not show increased toxicity compared with those age < 70 years, with similar rates of CRS, ICANS, and intensive care unit transfer. This study supports the role of axi-cel in the second-line setting, regardless of transplant eligibility.

Another important study recently published for patients with LBCL examined the role of central nervous system (CNS) prophylaxis (Lewis et al). We know that certain patients with LBCL, including those with a high CNS international prognostic index (IPI) score, double-hit lymphoma, or disease involvement of multiple or certain extranodal sites (ie, breast, testes, adrenals, kidney) can be at increased risk for lymphoma spread to the CNS.⁴ Strategies to reduce this risk have subsequently been developed for these high-risk patients, though consensus regarding who should be treated and how best to treat patients has been consistent. Recently, retrospective data have also called into question whether our current approaches meaningfully reduce this risk. One such study was a multicenter, international, retrospective observational study that included 2418 adults with aggressive LBCL and a high risk for CNS progression who were treated with curative-intent anti-CD20–based chemoimmunotherapy and who did or did not receive high-dose methotrexate (HD-MTX). Patients who did vs did not receive HD-MTX had a significantly lower risk for CNS progression (adjusted 5-year risk difference 1.6%; adjusted hazard ratio [aHR] 0.59; P = .014), but the significance was lost when considering only those patients who achieved a complete response at chemoimmunotherapy completion (adjusted 5-year risk difference 1.4%; aHR 0.74; P = .30). The study was not sufficiently powered to make definitive conclusions for individual risk groups, though there was no obvious reduction in CNS involvement risk in any high-risk subgroup. With an absolute risk reduction of 1.6% with the use of HD-MTX, 63 patients would require treatment to prevent one CNS progression event over 5 years (Lewis et al). Given the absence of prospective, randomized data, these results, though retrospective in nature, call into question the benefit of CNS prophylaxis. The authors suggest that studies evaluating alternative strategies for prophylaxis and tools for early detection of relapse, such as circulating tumor DNA, may be helpful.

Another study worth noting was one exploring Bruton tyrosine kinase (BTK) inhibition in mantle cell lymphoma (MCL). BTK inhibitors, including zanubrutinib, have emerged as effective therapies for patients with R/R disease. A recent pooled analysis included 112 patients from the BGB-3111-AU-003 and BGB-3111-206 clinical trials who had R/R MCL and received second-line (n = 41) or later-line (n = 71) zanubrutinib (Song et al). At a median follow-up of 35.2 months, patients receiving second-line vs later-line zanubrutinib had significantly improved median overall survival (aHR 0.459; P = .044) and numerically longer median progression-free survival (27.8 vs 22.1 months). Adverse events observed in both groups were consistent with the known safety profile of zanubrutinib. These findings were in line with a prior similar pooled study that demonstrated improved outcomes with second-line ibrutinib for patients with MCL as compared with later-line ibrutinib therapy.⁵ This study, however, did not evaluate the impact on CAR T–cell therapy in MCL, which is also an effective treatment option for patients with R/R disease, and how best to sequence with BTK inhibitors.

Additional References

1.       Locke FL, Miklos DB, Jacobson CA, et al, for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133

2.       Kamdar M, Solomon SR, Arnason J, et al, for theTRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. doi: 10.1016/S0140-6736(22)00662-6

3.       Gordon LI, Liu FF, Braverman J, et al. Lisocabtagene maraleucel for second-line relapsed or refractory large B-cell lymphoma: Patient-reported outcomes from the PILOT study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283162

4.       Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34:3150-3156. doi: 10.1200/JCO.2015.65.6520

5.       Dreyling M, Goy A, Hess G, et al. Long-term outcomes with ibrutinib treatment for patients with relapsed/refractory mantle cell lymphoma: A pooled analysis of 3 clinical trials with nearly 10 years of follow-up. Hemasphere. 2022;6:e712. doi: 10.1097/HS9.0000000000000712

Given the frequency of autoimmune conditions in women, the possible effects of estrogen and hormonal therapy exposure over the lifespan on the development of rheumatoid arthritis (RA) has long been of interest. Prior studies have identified a potential increase in RA risk in older women taking estrogen replacement. Hadizadeh and colleagues used the UK Biobank to identify cases of RA among over 236,000 women taking oral contraceptives and over 102,000 women taking hormone replacement therapy. Oral contraceptive use was associated with lower risk for RA (hazard ratio [HR] 0.89), whereas hormone replacement therapy was associated with higher risk for RA (HR 1.16) compared with women who had never used these therapies. Exogenous estrogen exposure may affect the development of RA, but the potential mechanisms (including the effect on systemic inflammation) remain unclear.

Among the multitude of studies on a treat-to-target (T2T) strategy in RA, a recent cluster randomized trial by Bessette and colleagues compared use of abatacept in 284 patients treated by 44 physicians. Patients assigned to both T2T and routine care had significant improvement in RA disease activity (as measured by the Clinical Disease Activity Index) with abatacept, with close to 40% in low disease activity at 12 months. Those treated with routine care experienced significant improvements in RA disease activity at 12 months of abatacept treatment. T2T was associated with slightly higher odds of low disease activity and a shorter time to Simplified Disease Activity Index remission (14 vs 19 months). With T2T being largely accepted as a standard of care on the basis of prior studies, this study raises the question of why little difference was seen between the two groups — perhaps it was related to the use of abatacept. It is unlikely to further change the standard of care to reduce use of disease activity measures.

To better understand refractory or difficult-to-treat (D2T) RA, Jung and colleagues used the KOBIO (KOrean College of Rheumatology BIOlogics) registry to compare characteristics of patients with D2T RA vs those who respond more readily to therapy. Of the 2321 patients included in the study, about 12% (271) had D2T RA. Patients with D2T RA tended to be younger and have longer disease duration, as well as a negative rheumatoid factor (RF); less use of conventional synthetic disease-modifying antirheumatic drugs (csDMARD); and, as expected, higher disease activity measures. Given that about 80% of patients were seropositive for RF and the fact that patients with D2T RA tended to have higher inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), it is not likely that patients were misclassified with RA. The reason why patients with D2T RA had less csDMARD use is not clear, but prior studies have supported early and aggressive use of csDMARD for best outcomes. The study did suggest that patients with D2T RA stayed on Janus kinase (JAK) inhibitor therapy the longest, and perhaps similar studies in future will help outline the best treatment strategy for patients with D2T RA and persistently high disease activity.

Finally, in a post hoc analysis of the ORAL Start trial of the JAK inhibitor tofacitinib vs methotrexate, Ciurea and colleagues looked at paired joint pathology scores (PJPS) — swollen and tender joint counts with left and right pooled — over the course of the 12-month study. Patients receiving tofacitinib had overall improved PJPS, though patients receiving methotrexate had more improvement in the foot. These findings, generally supporting those of the initial study, are unlikely to further change therapy.

Given the frequency of autoimmune conditions in women, the possible effects of estrogen and hormonal therapy exposure over the lifespan on the development of rheumatoid arthritis (RA) has long been of interest. Prior studies have identified a potential increase in RA risk in older women taking estrogen replacement. Hadizadeh and colleagues used the UK Biobank to identify cases of RA among over 236,000 women taking oral contraceptives and over 102,000 women taking hormone replacement therapy. Oral contraceptive use was associated with lower risk for RA (hazard ratio [HR] 0.89), whereas hormone replacement therapy was associated with higher risk for RA (HR 1.16) compared with women who had never used these therapies. Exogenous estrogen exposure may affect the development of RA, but the potential mechanisms (including the effect on systemic inflammation) remain unclear.

Among the multitude of studies on a treat-to-target (T2T) strategy in RA, a recent cluster randomized trial by Bessette and colleagues compared use of abatacept in 284 patients treated by 44 physicians. Patients assigned to both T2T and routine care had significant improvement in RA disease activity (as measured by the Clinical Disease Activity Index) with abatacept, with close to 40% in low disease activity at 12 months. Those treated with routine care experienced significant improvements in RA disease activity at 12 months of abatacept treatment. T2T was associated with slightly higher odds of low disease activity and a shorter time to Simplified Disease Activity Index remission (14 vs 19 months). With T2T being largely accepted as a standard of care on the basis of prior studies, this study raises the question of why little difference was seen between the two groups — perhaps it was related to the use of abatacept. It is unlikely to further change the standard of care to reduce use of disease activity measures.

To better understand refractory or difficult-to-treat (D2T) RA, Jung and colleagues used the KOBIO (KOrean College of Rheumatology BIOlogics) registry to compare characteristics of patients with D2T RA vs those who respond more readily to therapy. Of the 2321 patients included in the study, about 12% (271) had D2T RA. Patients with D2T RA tended to be younger and have longer disease duration, as well as a negative rheumatoid factor (RF); less use of conventional synthetic disease-modifying antirheumatic drugs (csDMARD); and, as expected, higher disease activity measures. Given that about 80% of patients were seropositive for RF and the fact that patients with D2T RA tended to have higher inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), it is not likely that patients were misclassified with RA. The reason why patients with D2T RA had less csDMARD use is not clear, but prior studies have supported early and aggressive use of csDMARD for best outcomes. The study did suggest that patients with D2T RA stayed on Janus kinase (JAK) inhibitor therapy the longest, and perhaps similar studies in future will help outline the best treatment strategy for patients with D2T RA and persistently high disease activity.

Finally, in a post hoc analysis of the ORAL Start trial of the JAK inhibitor tofacitinib vs methotrexate, Ciurea and colleagues looked at paired joint pathology scores (PJPS) — swollen and tender joint counts with left and right pooled — over the course of the 12-month study. Patients receiving tofacitinib had overall improved PJPS, though patients receiving methotrexate had more improvement in the foot. These findings, generally supporting those of the initial study, are unlikely to further change therapy.

Given the frequency of autoimmune conditions in women, the possible effects of estrogen and hormonal therapy exposure over the lifespan on the development of rheumatoid arthritis (RA) has long been of interest. Prior studies have identified a potential increase in RA risk in older women taking estrogen replacement. Hadizadeh and colleagues used the UK Biobank to identify cases of RA among over 236,000 women taking oral contraceptives and over 102,000 women taking hormone replacement therapy. Oral contraceptive use was associated with lower risk for RA (hazard ratio [HR] 0.89), whereas hormone replacement therapy was associated with higher risk for RA (HR 1.16) compared with women who had never used these therapies. Exogenous estrogen exposure may affect the development of RA, but the potential mechanisms (including the effect on systemic inflammation) remain unclear.

Among the multitude of studies on a treat-to-target (T2T) strategy in RA, a recent cluster randomized trial by Bessette and colleagues compared use of abatacept in 284 patients treated by 44 physicians. Patients assigned to both T2T and routine care had significant improvement in RA disease activity (as measured by the Clinical Disease Activity Index) with abatacept, with close to 40% in low disease activity at 12 months. Those treated with routine care experienced significant improvements in RA disease activity at 12 months of abatacept treatment. T2T was associated with slightly higher odds of low disease activity and a shorter time to Simplified Disease Activity Index remission (14 vs 19 months). With T2T being largely accepted as a standard of care on the basis of prior studies, this study raises the question of why little difference was seen between the two groups — perhaps it was related to the use of abatacept. It is unlikely to further change the standard of care to reduce use of disease activity measures.

To better understand refractory or difficult-to-treat (D2T) RA, Jung and colleagues used the KOBIO (KOrean College of Rheumatology BIOlogics) registry to compare characteristics of patients with D2T RA vs those who respond more readily to therapy. Of the 2321 patients included in the study, about 12% (271) had D2T RA. Patients with D2T RA tended to be younger and have longer disease duration, as well as a negative rheumatoid factor (RF); less use of conventional synthetic disease-modifying antirheumatic drugs (csDMARD); and, as expected, higher disease activity measures. Given that about 80% of patients were seropositive for RF and the fact that patients with D2T RA tended to have higher inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), it is not likely that patients were misclassified with RA. The reason why patients with D2T RA had less csDMARD use is not clear, but prior studies have supported early and aggressive use of csDMARD for best outcomes. The study did suggest that patients with D2T RA stayed on Janus kinase (JAK) inhibitor therapy the longest, and perhaps similar studies in future will help outline the best treatment strategy for patients with D2T RA and persistently high disease activity.

Finally, in a post hoc analysis of the ORAL Start trial of the JAK inhibitor tofacitinib vs methotrexate, Ciurea and colleagues looked at paired joint pathology scores (PJPS) — swollen and tender joint counts with left and right pooled — over the course of the 12-month study. Patients receiving tofacitinib had overall improved PJPS, though patients receiving methotrexate had more improvement in the foot. These findings, generally supporting those of the initial study, are unlikely to further change therapy.

In patients with node-positive and locally advanced breast cancer (BC), postmastectomy radiation therapy (PMRT) decreases risk for recurrence and improves survival (Mutter et al). Proton therapy is an attractive newer way to deliver PMRT compared with photon-based methods and allows improved sparing of cardiopulmonary and other normal tissue. The phase 2 MC1631 trial included 82 patients with BC who underwent mastectomy with or without immediate breast reconstruction and who were randomly assigned to receive either conventional fractionated (50 Gy in 25 fractions of 2 Gy) or hypofractionated (40.05 Gy in 15 fractions of 2.67 Gy) proton PMRT. At a median follow-up of 39.3 months, both conventional fractionated and hypofractionated proton PMRT had similar complication rates (15% vs 20%; absolute difference 4.9%; one-sided 95% CI 18.5; P = .27), with most complications occurring in patients with immediate expander or implant-based reconstruction. Noninferiority of the hypofractionation group could not be determined after a median follow-up of 39 months. However, no isolated local regional recurrences in either treatment arm were seen. This study provides the first prospective, randomized data of hypofractionated proton PMRT. Further data are awaited to support this approach. 

In patients with metastatic hormone receptor (HR)–positive, PIK3CA-mutant BC, the combination of fulvestrant with alpelisib improves progression-free survival per the SOLAR-1 study.1 Higher rates of hyperglycemia observed among patients treated with alpelisib have led to alpelisib dose reductions, treatment delays, and discontinuation of the drug. In a retrospective cohort study of 247 patients with metastatic BC who received alpelisib either as standard care (n = 147) or in a clinical trial setting (n = 100), 61.5% of patients developed any-grade hyperglycemia (Shen et al). The rate of hyperglycemia was considerably higher in patients who received alpelisib as part of standard care vs clinical trial (80.3% vs 34.0%). Baseline body mass index ≥ 25 (P = .036) and A1c levels in the prediabetes and diabetes range were significantly associated with the development of any-grade hyperglycemia (P = .036 and P < .001, respectively) and grade 3-4 hyperglycemia (P < .001 for both). A total of 4.5% of patients discontinued alpelisib owing to hyperglycemia, 17% of patients required dose reductions, and in 27% of patients alpelisib was held until resolution of hyperglycemia. This study highlights the importance of the management of comorbidities before alpelisib treatment to ensure lower rates of adverse events. 

Patritumab deruxtecan (HER3-DXd) is a novel HER3-targeted antibody-drug conjugate that is being evaluated in HER3-expressing metastatic BC. The U31402-A-J101 study is a phase 1/2 trial including 182 heavily pretreated patients (median of five prior therapies) with HER3-expressing advanced BC who received HER3-DXd (Krop et al). The objective response rate was 30.1% (95% CI 21.8%-39.4%) in HR-positive, human epidermal growth factor receptor 2 (HER2)–negative BC, 22.6% (95% CI 12.3%-36.2%) in triple-negative BC, and 42.9% (95% CI 17.1%-71.1%) in HER2-positive BC. Although 71.4% of patients reported grade ≥ 3 treatment-emergent adverse events (TEAE), the overall rate of treatment discontinuation due to TEAE was low (9.9%). These findings demonstrate an encouraging efficacy and a manageable safety profile for patritumab deruxtecan in previously treated patients with BC across all subtypes. Further studies are awaited to confirm these findings and whether prior treatment with antibody-drug conjugate will affect the activity of this drug.

A retrospective analysis of a cohort including 149 patients with metastatic BC looked at predictors of prognosis in patients who had brain metastases and underwent stereotactic radiosurgery (Depner et al). The median overall survival was 14.8 months for the entire cohort. Receptor profiles and the presence of extracranial visceral metastases were significant predictors of prognosis. Overall survival outcomes worsened in patients with estrogen receptor (ER)–negative, HER2-negative BC (hazard ratio 2.00; 95% CI 1.09-3.67) but were better in those with ER-positive, HER2-positive BC (hazard ratio 0.43; 95% CI 0.19-0.96). Furthermore, the presence of extracranial visceral metastases was associated with poor survival outcomes (hazard ratio 2.90; 95% CI 1.53-5.50)

Additional Reference
1.    André F et al, for the SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940. doi: 10.1056/NEJMoa1813904
 

In patients with node-positive and locally advanced breast cancer (BC), postmastectomy radiation therapy (PMRT) decreases risk for recurrence and improves survival (Mutter et al). Proton therapy is an attractive newer way to deliver PMRT compared with photon-based methods and allows improved sparing of cardiopulmonary and other normal tissue. The phase 2 MC1631 trial included 82 patients with BC who underwent mastectomy with or without immediate breast reconstruction and who were randomly assigned to receive either conventional fractionated (50 Gy in 25 fractions of 2 Gy) or hypofractionated (40.05 Gy in 15 fractions of 2.67 Gy) proton PMRT. At a median follow-up of 39.3 months, both conventional fractionated and hypofractionated proton PMRT had similar complication rates (15% vs 20%; absolute difference 4.9%; one-sided 95% CI 18.5; P = .27), with most complications occurring in patients with immediate expander or implant-based reconstruction. Noninferiority of the hypofractionation group could not be determined after a median follow-up of 39 months. However, no isolated local regional recurrences in either treatment arm were seen. This study provides the first prospective, randomized data of hypofractionated proton PMRT. Further data are awaited to support this approach. 

In patients with metastatic hormone receptor (HR)–positive, PIK3CA-mutant BC, the combination of fulvestrant with alpelisib improves progression-free survival per the SOLAR-1 study.1 Higher rates of hyperglycemia observed among patients treated with alpelisib have led to alpelisib dose reductions, treatment delays, and discontinuation of the drug. In a retrospective cohort study of 247 patients with metastatic BC who received alpelisib either as standard care (n = 147) or in a clinical trial setting (n = 100), 61.5% of patients developed any-grade hyperglycemia (Shen et al). The rate of hyperglycemia was considerably higher in patients who received alpelisib as part of standard care vs clinical trial (80.3% vs 34.0%). Baseline body mass index ≥ 25 (P = .036) and A1c levels in the prediabetes and diabetes range were significantly associated with the development of any-grade hyperglycemia (P = .036 and P < .001, respectively) and grade 3-4 hyperglycemia (P < .001 for both). A total of 4.5% of patients discontinued alpelisib owing to hyperglycemia, 17% of patients required dose reductions, and in 27% of patients alpelisib was held until resolution of hyperglycemia. This study highlights the importance of the management of comorbidities before alpelisib treatment to ensure lower rates of adverse events. 

Patritumab deruxtecan (HER3-DXd) is a novel HER3-targeted antibody-drug conjugate that is being evaluated in HER3-expressing metastatic BC. The U31402-A-J101 study is a phase 1/2 trial including 182 heavily pretreated patients (median of five prior therapies) with HER3-expressing advanced BC who received HER3-DXd (Krop et al). The objective response rate was 30.1% (95% CI 21.8%-39.4%) in HR-positive, human epidermal growth factor receptor 2 (HER2)–negative BC, 22.6% (95% CI 12.3%-36.2%) in triple-negative BC, and 42.9% (95% CI 17.1%-71.1%) in HER2-positive BC. Although 71.4% of patients reported grade ≥ 3 treatment-emergent adverse events (TEAE), the overall rate of treatment discontinuation due to TEAE was low (9.9%). These findings demonstrate an encouraging efficacy and a manageable safety profile for patritumab deruxtecan in previously treated patients with BC across all subtypes. Further studies are awaited to confirm these findings and whether prior treatment with antibody-drug conjugate will affect the activity of this drug.

A retrospective analysis of a cohort including 149 patients with metastatic BC looked at predictors of prognosis in patients who had brain metastases and underwent stereotactic radiosurgery (Depner et al). The median overall survival was 14.8 months for the entire cohort. Receptor profiles and the presence of extracranial visceral metastases were significant predictors of prognosis. Overall survival outcomes worsened in patients with estrogen receptor (ER)–negative, HER2-negative BC (hazard ratio 2.00; 95% CI 1.09-3.67) but were better in those with ER-positive, HER2-positive BC (hazard ratio 0.43; 95% CI 0.19-0.96). Furthermore, the presence of extracranial visceral metastases was associated with poor survival outcomes (hazard ratio 2.90; 95% CI 1.53-5.50)

Additional Reference
1.    André F et al, for the SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940. doi: 10.1056/NEJMoa1813904
 

In patients with node-positive and locally advanced breast cancer (BC), postmastectomy radiation therapy (PMRT) decreases risk for recurrence and improves survival (Mutter et al). Proton therapy is an attractive newer way to deliver PMRT compared with photon-based methods and allows improved sparing of cardiopulmonary and other normal tissue. The phase 2 MC1631 trial included 82 patients with BC who underwent mastectomy with or without immediate breast reconstruction and who were randomly assigned to receive either conventional fractionated (50 Gy in 25 fractions of 2 Gy) or hypofractionated (40.05 Gy in 15 fractions of 2.67 Gy) proton PMRT. At a median follow-up of 39.3 months, both conventional fractionated and hypofractionated proton PMRT had similar complication rates (15% vs 20%; absolute difference 4.9%; one-sided 95% CI 18.5; P = .27), with most complications occurring in patients with immediate expander or implant-based reconstruction. Noninferiority of the hypofractionation group could not be determined after a median follow-up of 39 months. However, no isolated local regional recurrences in either treatment arm were seen. This study provides the first prospective, randomized data of hypofractionated proton PMRT. Further data are awaited to support this approach. 

In patients with metastatic hormone receptor (HR)–positive, PIK3CA-mutant BC, the combination of fulvestrant with alpelisib improves progression-free survival per the SOLAR-1 study.1 Higher rates of hyperglycemia observed among patients treated with alpelisib have led to alpelisib dose reductions, treatment delays, and discontinuation of the drug. In a retrospective cohort study of 247 patients with metastatic BC who received alpelisib either as standard care (n = 147) or in a clinical trial setting (n = 100), 61.5% of patients developed any-grade hyperglycemia (Shen et al). The rate of hyperglycemia was considerably higher in patients who received alpelisib as part of standard care vs clinical trial (80.3% vs 34.0%). Baseline body mass index ≥ 25 (P = .036) and A1c levels in the prediabetes and diabetes range were significantly associated with the development of any-grade hyperglycemia (P = .036 and P < .001, respectively) and grade 3-4 hyperglycemia (P < .001 for both). A total of 4.5% of patients discontinued alpelisib owing to hyperglycemia, 17% of patients required dose reductions, and in 27% of patients alpelisib was held until resolution of hyperglycemia. This study highlights the importance of the management of comorbidities before alpelisib treatment to ensure lower rates of adverse events. 

Patritumab deruxtecan (HER3-DXd) is a novel HER3-targeted antibody-drug conjugate that is being evaluated in HER3-expressing metastatic BC. The U31402-A-J101 study is a phase 1/2 trial including 182 heavily pretreated patients (median of five prior therapies) with HER3-expressing advanced BC who received HER3-DXd (Krop et al). The objective response rate was 30.1% (95% CI 21.8%-39.4%) in HR-positive, human epidermal growth factor receptor 2 (HER2)–negative BC, 22.6% (95% CI 12.3%-36.2%) in triple-negative BC, and 42.9% (95% CI 17.1%-71.1%) in HER2-positive BC. Although 71.4% of patients reported grade ≥ 3 treatment-emergent adverse events (TEAE), the overall rate of treatment discontinuation due to TEAE was low (9.9%). These findings demonstrate an encouraging efficacy and a manageable safety profile for patritumab deruxtecan in previously treated patients with BC across all subtypes. Further studies are awaited to confirm these findings and whether prior treatment with antibody-drug conjugate will affect the activity of this drug.

A retrospective analysis of a cohort including 149 patients with metastatic BC looked at predictors of prognosis in patients who had brain metastases and underwent stereotactic radiosurgery (Depner et al). The median overall survival was 14.8 months for the entire cohort. Receptor profiles and the presence of extracranial visceral metastases were significant predictors of prognosis. Overall survival outcomes worsened in patients with estrogen receptor (ER)–negative, HER2-negative BC (hazard ratio 2.00; 95% CI 1.09-3.67) but were better in those with ER-positive, HER2-positive BC (hazard ratio 0.43; 95% CI 0.19-0.96). Furthermore, the presence of extracranial visceral metastases was associated with poor survival outcomes (hazard ratio 2.90; 95% CI 1.53-5.50)

Additional Reference
1.    André F et al, for the SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940. doi: 10.1056/NEJMoa1813904
 

Flohr and colleagues present the results of a controlled trial of cyclosporine vs methotrexate for severe atopic dermatitis ("Efficacy and Safety of Ciclosporin Versus Methotrexate in the Treatment of Severe Atopic Dermatitis in Children and Young People"). Cyclosporine worked faster, yet methotrexate was a bit more effective in the long run. Both treatments had considerable side effects; 10% and 14% had serious events with cyclosporine and methotrexate, respectively. My only quibble is with the first word of the abstract background section; the authors call cyclosporine and methotrexate "conventional" systemic drugs for atopic dermatitis. At this point, considering safety and efficacy, I would consider drugs like dupilumab to be the "conventional" systemic treatment for atopic dermatitis.

Wan and colleagues ("Neuropsychiatric Disorders in Adults With Atopic Dermatitis") present an exceptionally well-done study with a huge patient population. The study compared about 600,000 adults with atopic dermatitis vs over 2,000,000 adults without the disease. A sample size like that offers a lot of power to detect very small differences between groups. The researchers report higher rates of anxiety and depression in patients with atopic dermatitis compared to those without. Are those differences clinically meaningfully different? The rates of depression were 14 and 17 cases per 1000 patient-years for those without and those with severe atopic dermatitis, respectively. That's a difference of 3 per 1000 patient-years. So maybe roughly 300 patients with atopic dermatitis would need to be seen to observe one patient with depression due to atopic dermatitis (assuming that the observed differences in rates between those with and those without atopic dermatitis were due to the dermatitis). The authors conclude, "Clinicians should inquire about mental health in patients with AD." I don't think their data support such a conclusion. We'd need to see a cost-effectiveness study to know if that's an intervention that we should do. Given the very small difference between the rates in those with and those without atopic dermatitis, it might be reasonable to conclude that we should inquire about mental health in patients with atopic dermatitis about as much as we should in patients without atopic dermatitis.

Some years ago, there was an over-the-counter topical product for psoriasis based on a banana peel extract. I think it was marketed as "FDA approved" for psoriasis (which was legal to say because the product also contained tar) and as being as effective as topical calcipotriene as published in the Journal of Investigational Dermatology (JID). I went to look for the article; the "publication" was the abstract of a poster presentation. The study followed a very small study population for a short period of time. The study was, I believe, underpowered to detect differences between the banana peel extract and the vitamin D analog. Those data were presented as a poster, the poster abstracts were printed in JID, and, voilà, the product was marketed as being as effective as topical calcipotriene as published in JID.

Sowlati and colleagues ("Efficacy and Tolerability of a Novel Topical Treatment Containing Pea Protein and Xyloglucan in the Management of Atopic Dermatitis in Children") randomly assigned 42 patients to receive either a xyloglucan/pea protein topical therapy or hydrocortisone. The participants were followed for 2 weeks. Both groups improved. We don't know whether they improved more than they would have with moisturizer. This study doesn't make me excited about prescribing the xyloglucan/pea protein topical.

The study by Mohamed and colleagues comparing tacrolimus and hydrocortisone reminds me that we have an effective generic topical anti-inflammatory for our patients with atopic dermatitis. Given the safety of topical tacrolimus, I prefer prescribing the 0.1% ointment for all my patients, though I give the lower concentration, approved for children, if the insurer makes me.

Simpson and colleagues' post hoc analysis of tralokinumab tells us that, with continued use, some patients who don't respond well initially will have greater improvement. But what I'd really like to see is a head-to-head study comparing tralokinumab vs dupilumab. Dupilumab seems to have stronger efficacy based on their reported trial numbers, but a head-to-head trial would give us greater confidence in their relative benefits.

I have trouble getting excited about this study by Cork and colleagues ("Dupilumab Safety and Efficacy in a Phase III Open-Label Extension Trial in Children 6-11 Years of Age With Severe Atopic Dermatitis"). I feel very comfortable with dupilumab already.

Flohr and colleagues present the results of a controlled trial of cyclosporine vs methotrexate for severe atopic dermatitis ("Efficacy and Safety of Ciclosporin Versus Methotrexate in the Treatment of Severe Atopic Dermatitis in Children and Young People"). Cyclosporine worked faster, yet methotrexate was a bit more effective in the long run. Both treatments had considerable side effects; 10% and 14% had serious events with cyclosporine and methotrexate, respectively. My only quibble is with the first word of the abstract background section; the authors call cyclosporine and methotrexate "conventional" systemic drugs for atopic dermatitis. At this point, considering safety and efficacy, I would consider drugs like dupilumab to be the "conventional" systemic treatment for atopic dermatitis.

Wan and colleagues ("Neuropsychiatric Disorders in Adults With Atopic Dermatitis") present an exceptionally well-done study with a huge patient population. The study compared about 600,000 adults with atopic dermatitis vs over 2,000,000 adults without the disease. A sample size like that offers a lot of power to detect very small differences between groups. The researchers report higher rates of anxiety and depression in patients with atopic dermatitis compared to those without. Are those differences clinically meaningfully different? The rates of depression were 14 and 17 cases per 1000 patient-years for those without and those with severe atopic dermatitis, respectively. That's a difference of 3 per 1000 patient-years. So maybe roughly 300 patients with atopic dermatitis would need to be seen to observe one patient with depression due to atopic dermatitis (assuming that the observed differences in rates between those with and those without atopic dermatitis were due to the dermatitis). The authors conclude, "Clinicians should inquire about mental health in patients with AD." I don't think their data support such a conclusion. We'd need to see a cost-effectiveness study to know if that's an intervention that we should do. Given the very small difference between the rates in those with and those without atopic dermatitis, it might be reasonable to conclude that we should inquire about mental health in patients with atopic dermatitis about as much as we should in patients without atopic dermatitis.

Some years ago, there was an over-the-counter topical product for psoriasis based on a banana peel extract. I think it was marketed as "FDA approved" for psoriasis (which was legal to say because the product also contained tar) and as being as effective as topical calcipotriene as published in the Journal of Investigational Dermatology (JID). I went to look for the article; the "publication" was the abstract of a poster presentation. The study followed a very small study population for a short period of time. The study was, I believe, underpowered to detect differences between the banana peel extract and the vitamin D analog. Those data were presented as a poster, the poster abstracts were printed in JID, and, voilà, the product was marketed as being as effective as topical calcipotriene as published in JID.

Sowlati and colleagues ("Efficacy and Tolerability of a Novel Topical Treatment Containing Pea Protein and Xyloglucan in the Management of Atopic Dermatitis in Children") randomly assigned 42 patients to receive either a xyloglucan/pea protein topical therapy or hydrocortisone. The participants were followed for 2 weeks. Both groups improved. We don't know whether they improved more than they would have with moisturizer. This study doesn't make me excited about prescribing the xyloglucan/pea protein topical.

The study by Mohamed and colleagues comparing tacrolimus and hydrocortisone reminds me that we have an effective generic topical anti-inflammatory for our patients with atopic dermatitis. Given the safety of topical tacrolimus, I prefer prescribing the 0.1% ointment for all my patients, though I give the lower concentration, approved for children, if the insurer makes me.

Simpson and colleagues' post hoc analysis of tralokinumab tells us that, with continued use, some patients who don't respond well initially will have greater improvement. But what I'd really like to see is a head-to-head study comparing tralokinumab vs dupilumab. Dupilumab seems to have stronger efficacy based on their reported trial numbers, but a head-to-head trial would give us greater confidence in their relative benefits.

I have trouble getting excited about this study by Cork and colleagues ("Dupilumab Safety and Efficacy in a Phase III Open-Label Extension Trial in Children 6-11 Years of Age With Severe Atopic Dermatitis"). I feel very comfortable with dupilumab already.

Flohr and colleagues present the results of a controlled trial of cyclosporine vs methotrexate for severe atopic dermatitis ("Efficacy and Safety of Ciclosporin Versus Methotrexate in the Treatment of Severe Atopic Dermatitis in Children and Young People"). Cyclosporine worked faster, yet methotrexate was a bit more effective in the long run. Both treatments had considerable side effects; 10% and 14% had serious events with cyclosporine and methotrexate, respectively. My only quibble is with the first word of the abstract background section; the authors call cyclosporine and methotrexate "conventional" systemic drugs for atopic dermatitis. At this point, considering safety and efficacy, I would consider drugs like dupilumab to be the "conventional" systemic treatment for atopic dermatitis.

Wan and colleagues ("Neuropsychiatric Disorders in Adults With Atopic Dermatitis") present an exceptionally well-done study with a huge patient population. The study compared about 600,000 adults with atopic dermatitis vs over 2,000,000 adults without the disease. A sample size like that offers a lot of power to detect very small differences between groups. The researchers report higher rates of anxiety and depression in patients with atopic dermatitis compared to those without. Are those differences clinically meaningfully different? The rates of depression were 14 and 17 cases per 1000 patient-years for those without and those with severe atopic dermatitis, respectively. That's a difference of 3 per 1000 patient-years. So maybe roughly 300 patients with atopic dermatitis would need to be seen to observe one patient with depression due to atopic dermatitis (assuming that the observed differences in rates between those with and those without atopic dermatitis were due to the dermatitis). The authors conclude, "Clinicians should inquire about mental health in patients with AD." I don't think their data support such a conclusion. We'd need to see a cost-effectiveness study to know if that's an intervention that we should do. Given the very small difference between the rates in those with and those without atopic dermatitis, it might be reasonable to conclude that we should inquire about mental health in patients with atopic dermatitis about as much as we should in patients without atopic dermatitis.

Some years ago, there was an over-the-counter topical product for psoriasis based on a banana peel extract. I think it was marketed as "FDA approved" for psoriasis (which was legal to say because the product also contained tar) and as being as effective as topical calcipotriene as published in the Journal of Investigational Dermatology (JID). I went to look for the article; the "publication" was the abstract of a poster presentation. The study followed a very small study population for a short period of time. The study was, I believe, underpowered to detect differences between the banana peel extract and the vitamin D analog. Those data were presented as a poster, the poster abstracts were printed in JID, and, voilà, the product was marketed as being as effective as topical calcipotriene as published in JID.

Sowlati and colleagues ("Efficacy and Tolerability of a Novel Topical Treatment Containing Pea Protein and Xyloglucan in the Management of Atopic Dermatitis in Children") randomly assigned 42 patients to receive either a xyloglucan/pea protein topical therapy or hydrocortisone. The participants were followed for 2 weeks. Both groups improved. We don't know whether they improved more than they would have with moisturizer. This study doesn't make me excited about prescribing the xyloglucan/pea protein topical.

The study by Mohamed and colleagues comparing tacrolimus and hydrocortisone reminds me that we have an effective generic topical anti-inflammatory for our patients with atopic dermatitis. Given the safety of topical tacrolimus, I prefer prescribing the 0.1% ointment for all my patients, though I give the lower concentration, approved for children, if the insurer makes me.

Simpson and colleagues' post hoc analysis of tralokinumab tells us that, with continued use, some patients who don't respond well initially will have greater improvement. But what I'd really like to see is a head-to-head study comparing tralokinumab vs dupilumab. Dupilumab seems to have stronger efficacy based on their reported trial numbers, but a head-to-head trial would give us greater confidence in their relative benefits.

I have trouble getting excited about this study by Cork and colleagues ("Dupilumab Safety and Efficacy in a Phase III Open-Label Extension Trial in Children 6-11 Years of Age With Severe Atopic Dermatitis"). I feel very comfortable with dupilumab already.

Key clinical point: Methotrexate remains the anchor untargeted conventional treatment for rheumatoid arthritis (RA); however, several alternatives are now available in case of suboptimal outcomes or unacceptable adverse events with methotrexate.

Major finding: Methotrexate reduced the imputed tender joint count (TJCi) by 5.18 joints (95% credible interval [CrI] 4.07-6.28 joints) compared with placebo. Cyclophosphamide fared better than methotrexate in terms of TJCi reduction (6.08 joints; 95% CrI 0.44-11.66 joints), but glucocorticoids (−2.54 joints; 95% CrI −5.16 to 0.08 joints) and the remaining drugs showed similar or lower reductions in the TJCi.

Study details: Findings are from a network meta-analysis of 29 interventions investigated in 132 randomized clinical trials including 13,260 patients with RA who were randomly assigned to receive conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids, placebo, or a pharmacologic non-disease-modifying comparator.

Disclosures: This study was funded by grants from the Danish Regions Medicine Fund and other sources. The authors declared no conflicts of interest.

Source: Guski LS et al. Monotreatment with conventional antirheumatic drugs or glucocorticoids in rheumatoid arthritis: A network meta-analysis. JAMA Netw Open. 2023;6(10):e2335950 (Oct 6). doi: 10.1001/jamanetworkopen.2023.35950

Key clinical point: Methotrexate remains the anchor untargeted conventional treatment for rheumatoid arthritis (RA); however, several alternatives are now available in case of suboptimal outcomes or unacceptable adverse events with methotrexate.

Major finding: Methotrexate reduced the imputed tender joint count (TJCi) by 5.18 joints (95% credible interval [CrI] 4.07-6.28 joints) compared with placebo. Cyclophosphamide fared better than methotrexate in terms of TJCi reduction (6.08 joints; 95% CrI 0.44-11.66 joints), but glucocorticoids (−2.54 joints; 95% CrI −5.16 to 0.08 joints) and the remaining drugs showed similar or lower reductions in the TJCi.

Study details: Findings are from a network meta-analysis of 29 interventions investigated in 132 randomized clinical trials including 13,260 patients with RA who were randomly assigned to receive conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids, placebo, or a pharmacologic non-disease-modifying comparator.

Disclosures: This study was funded by grants from the Danish Regions Medicine Fund and other sources. The authors declared no conflicts of interest.

Source: Guski LS et al. Monotreatment with conventional antirheumatic drugs or glucocorticoids in rheumatoid arthritis: A network meta-analysis. JAMA Netw Open. 2023;6(10):e2335950 (Oct 6). doi: 10.1001/jamanetworkopen.2023.35950

Key clinical point: Methotrexate remains the anchor untargeted conventional treatment for rheumatoid arthritis (RA); however, several alternatives are now available in case of suboptimal outcomes or unacceptable adverse events with methotrexate.

Major finding: Methotrexate reduced the imputed tender joint count (TJCi) by 5.18 joints (95% credible interval [CrI] 4.07-6.28 joints) compared with placebo. Cyclophosphamide fared better than methotrexate in terms of TJCi reduction (6.08 joints; 95% CrI 0.44-11.66 joints), but glucocorticoids (−2.54 joints; 95% CrI −5.16 to 0.08 joints) and the remaining drugs showed similar or lower reductions in the TJCi.

Study details: Findings are from a network meta-analysis of 29 interventions investigated in 132 randomized clinical trials including 13,260 patients with RA who were randomly assigned to receive conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids, placebo, or a pharmacologic non-disease-modifying comparator.

Disclosures: This study was funded by grants from the Danish Regions Medicine Fund and other sources. The authors declared no conflicts of interest.

Source: Guski LS et al. Monotreatment with conventional antirheumatic drugs or glucocorticoids in rheumatoid arthritis: A network meta-analysis. JAMA Netw Open. 2023;6(10):e2335950 (Oct 6). doi: 10.1001/jamanetworkopen.2023.35950

Key clinical point: The risk for cardiovascular events was similar with Janus kinase inhibitors (JAKi) and biologic disease-modifying antirheumatic drugs (bDMARD) in patients with rheumatoid arthritis (RA), although the risk may be slightly higher in elderly patients.

Major finding: JAKi vs bDMARD were not associated with a significantly different risk for cardiovascular events (adjusted incidence rate ratio [aIRR] 1.01; P  =  .965), but with a trend for a higher cardiovascular risk among patients > 65 years old (aIRR 1.24; 95% CI 0.80-1.91) and a lower risk among patients < 65 years old (aIRR 0.70; 95% CI 0.39-1.28).

Study details: Findings are from a retrospective inception cohort study including 15,191 patients with RA from the IQVIA’s Real-World Data Longitudinal Prescription database who had started a new bDMARD or JAKi.

Disclosures: This study was supported by an unrestricted educational grant from Pfizer BV. Two authors declared receiving past grants to the institution from various sources, including Pfizer. The other authors declared no conflicts of interest.

Source: Popa CD et al. Therapy with JAK inhibitors or bDMARDs and the risk of cardiovascular events in the Dutch rheumatoid arthritis population. Rheumatology (Oxford). 2023 (Oct 5). doi: 10.1093/rheumatology/kead531

Key clinical point: The risk for cardiovascular events was similar with Janus kinase inhibitors (JAKi) and biologic disease-modifying antirheumatic drugs (bDMARD) in patients with rheumatoid arthritis (RA), although the risk may be slightly higher in elderly patients.

Major finding: JAKi vs bDMARD were not associated with a significantly different risk for cardiovascular events (adjusted incidence rate ratio [aIRR] 1.01; P  =  .965), but with a trend for a higher cardiovascular risk among patients > 65 years old (aIRR 1.24; 95% CI 0.80-1.91) and a lower risk among patients < 65 years old (aIRR 0.70; 95% CI 0.39-1.28).

Study details: Findings are from a retrospective inception cohort study including 15,191 patients with RA from the IQVIA’s Real-World Data Longitudinal Prescription database who had started a new bDMARD or JAKi.

Disclosures: This study was supported by an unrestricted educational grant from Pfizer BV. Two authors declared receiving past grants to the institution from various sources, including Pfizer. The other authors declared no conflicts of interest.

Source: Popa CD et al. Therapy with JAK inhibitors or bDMARDs and the risk of cardiovascular events in the Dutch rheumatoid arthritis population. Rheumatology (Oxford). 2023 (Oct 5). doi: 10.1093/rheumatology/kead531

Key clinical point: The risk for cardiovascular events was similar with Janus kinase inhibitors (JAKi) and biologic disease-modifying antirheumatic drugs (bDMARD) in patients with rheumatoid arthritis (RA), although the risk may be slightly higher in elderly patients.

Major finding: JAKi vs bDMARD were not associated with a significantly different risk for cardiovascular events (adjusted incidence rate ratio [aIRR] 1.01; P  =  .965), but with a trend for a higher cardiovascular risk among patients > 65 years old (aIRR 1.24; 95% CI 0.80-1.91) and a lower risk among patients < 65 years old (aIRR 0.70; 95% CI 0.39-1.28).

Study details: Findings are from a retrospective inception cohort study including 15,191 patients with RA from the IQVIA’s Real-World Data Longitudinal Prescription database who had started a new bDMARD or JAKi.

Disclosures: This study was supported by an unrestricted educational grant from Pfizer BV. Two authors declared receiving past grants to the institution from various sources, including Pfizer. The other authors declared no conflicts of interest.

Source: Popa CD et al. Therapy with JAK inhibitors or bDMARDs and the risk of cardiovascular events in the Dutch rheumatoid arthritis population. Rheumatology (Oxford). 2023 (Oct 5). doi: 10.1093/rheumatology/kead531

Key clinical point: Patients with difficult-to-treat (D2T) rheumatoid arthritis (RA) had a higher disease activity despite treatment with biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARD) and demonstrated higher withdrawal rates due to inefficacy.

Major finding: Patients with vs without D2T RA had a higher Simplified Disease Activity Index (SDAI; P  =  .003) and higher withdrawal rates for b/tsDMARD due to inefficacy (P < .001). Higher SDAI (adjusted odds ratio [aOR] 1.06; P  =  .014), longer disease duration (aOR 1.06; P < .001), and lower prior use of methotrexate (aOR 0.44; P  =  .008), sulfasalazine (aOR 0.59; P  =  .003), and leflunomide (aOR 0.67; P  =  .013) were associated with D2T RA.

Study details: Findings are from a retrospective study including 2321 patients with RA from the Korean College of Rheumatology Biologics Registry who initiated or switched to b/tsDMARD, of which 271 patients had D2T RA.

Disclosures: This study was supported by a grant from the Yuhan Corporation, Seoul. The authors declared no conflicts of interest.

Source: Jung J-Y et al. Unveiling difficult-to-treat rheumatoid arthritis: Long-term impact of biologic or targeted synthetic DMARDs from the KOBIO registry. Arthritis Res Ther. 2023;25:174 (Sep 19). doi: 10.1186/s13075-023-03165-w

Key clinical point: Patients with difficult-to-treat (D2T) rheumatoid arthritis (RA) had a higher disease activity despite treatment with biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARD) and demonstrated higher withdrawal rates due to inefficacy.

Major finding: Patients with vs without D2T RA had a higher Simplified Disease Activity Index (SDAI; P  =  .003) and higher withdrawal rates for b/tsDMARD due to inefficacy (P < .001). Higher SDAI (adjusted odds ratio [aOR] 1.06; P  =  .014), longer disease duration (aOR 1.06; P < .001), and lower prior use of methotrexate (aOR 0.44; P  =  .008), sulfasalazine (aOR 0.59; P  =  .003), and leflunomide (aOR 0.67; P  =  .013) were associated with D2T RA.

Study details: Findings are from a retrospective study including 2321 patients with RA from the Korean College of Rheumatology Biologics Registry who initiated or switched to b/tsDMARD, of which 271 patients had D2T RA.

Disclosures: This study was supported by a grant from the Yuhan Corporation, Seoul. The authors declared no conflicts of interest.

Source: Jung J-Y et al. Unveiling difficult-to-treat rheumatoid arthritis: Long-term impact of biologic or targeted synthetic DMARDs from the KOBIO registry. Arthritis Res Ther. 2023;25:174 (Sep 19). doi: 10.1186/s13075-023-03165-w

Key clinical point: Patients with difficult-to-treat (D2T) rheumatoid arthritis (RA) had a higher disease activity despite treatment with biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARD) and demonstrated higher withdrawal rates due to inefficacy.

Major finding: Patients with vs without D2T RA had a higher Simplified Disease Activity Index (SDAI; P  =  .003) and higher withdrawal rates for b/tsDMARD due to inefficacy (P < .001). Higher SDAI (adjusted odds ratio [aOR] 1.06; P  =  .014), longer disease duration (aOR 1.06; P < .001), and lower prior use of methotrexate (aOR 0.44; P  =  .008), sulfasalazine (aOR 0.59; P  =  .003), and leflunomide (aOR 0.67; P  =  .013) were associated with D2T RA.

Study details: Findings are from a retrospective study including 2321 patients with RA from the Korean College of Rheumatology Biologics Registry who initiated or switched to b/tsDMARD, of which 271 patients had D2T RA.

Disclosures: This study was supported by a grant from the Yuhan Corporation, Seoul. The authors declared no conflicts of interest.

Source: Jung J-Y et al. Unveiling difficult-to-treat rheumatoid arthritis: Long-term impact of biologic or targeted synthetic DMARDs from the KOBIO registry. Arthritis Res Ther. 2023;25:174 (Sep 19). doi: 10.1186/s13075-023-03165-w

Key clinical point: Methotrexate-naive patients with rheumatoid arthritis (RA) showed varied joint-specific clinical responses to tofacitinib and methotrexate monotherapies, with those receiving methotrexate demonstrating more radiographic progression in the foot joints despite improved clinical response.

Major finding: At 12 months, tofacitinib vs methotrexate improved the clinical response in most tender and swollen joints, except some foot joints. Methotrexate improved the clinical response in most foot joints; however, radiographic progression was significantly worse with methotrexate vs tofacitinib (P < .05).

Study details: Findings are from a post hoc analysis of the phase 3 ORAL Start trial including 956 methotrexate-naive patients with RA who were randomly assigned to receive monotherapy with 5 mg (n = 373) or 10 mg (n = 397) tofacitinib or methotrexate (n = 186).

Disclosures: This study was sponsored by Pfizer, Inc. Four authors declared being current or former employees or shareholders of Pfizer or Syneos Health. Some authors declared receiving grants, honoraria, or research funding or having other ties with various sources, including Pfizer.

Source: Ciurea A et al. Joint-level responses to tofacitinib and methotrexate: A post hoc analysis of data from ORAL Start. Arthritis Res Ther. 2023;25:185 (Sep 29). doi: 10.1186/s13075-023-03144-1

Key clinical point: Methotrexate-naive patients with rheumatoid arthritis (RA) showed varied joint-specific clinical responses to tofacitinib and methotrexate monotherapies, with those receiving methotrexate demonstrating more radiographic progression in the foot joints despite improved clinical response.

Major finding: At 12 months, tofacitinib vs methotrexate improved the clinical response in most tender and swollen joints, except some foot joints. Methotrexate improved the clinical response in most foot joints; however, radiographic progression was significantly worse with methotrexate vs tofacitinib (P < .05).

Study details: Findings are from a post hoc analysis of the phase 3 ORAL Start trial including 956 methotrexate-naive patients with RA who were randomly assigned to receive monotherapy with 5 mg (n = 373) or 10 mg (n = 397) tofacitinib or methotrexate (n = 186).

Disclosures: This study was sponsored by Pfizer, Inc. Four authors declared being current or former employees or shareholders of Pfizer or Syneos Health. Some authors declared receiving grants, honoraria, or research funding or having other ties with various sources, including Pfizer.

Source: Ciurea A et al. Joint-level responses to tofacitinib and methotrexate: A post hoc analysis of data from ORAL Start. Arthritis Res Ther. 2023;25:185 (Sep 29). doi: 10.1186/s13075-023-03144-1

Key clinical point: Methotrexate-naive patients with rheumatoid arthritis (RA) showed varied joint-specific clinical responses to tofacitinib and methotrexate monotherapies, with those receiving methotrexate demonstrating more radiographic progression in the foot joints despite improved clinical response.

Major finding: At 12 months, tofacitinib vs methotrexate improved the clinical response in most tender and swollen joints, except some foot joints. Methotrexate improved the clinical response in most foot joints; however, radiographic progression was significantly worse with methotrexate vs tofacitinib (P < .05).

Study details: Findings are from a post hoc analysis of the phase 3 ORAL Start trial including 956 methotrexate-naive patients with RA who were randomly assigned to receive monotherapy with 5 mg (n = 373) or 10 mg (n = 397) tofacitinib or methotrexate (n = 186).

Disclosures: This study was sponsored by Pfizer, Inc. Four authors declared being current or former employees or shareholders of Pfizer or Syneos Health. Some authors declared receiving grants, honoraria, or research funding or having other ties with various sources, including Pfizer.

Source: Ciurea A et al. Joint-level responses to tofacitinib and methotrexate: A post hoc analysis of data from ORAL Start. Arthritis Res Ther. 2023;25:185 (Sep 29). doi: 10.1186/s13075-023-03144-1

Key clinical point: Younger age, higher disease activity, prevalent erosions, and monotherapy were significant risk factors for the development of new bone erosions in biologic disease-modifying antirheumatic drug (bDMARD)-treated patients with rheumatoid arthritis (RA).

Major finding: Risk of developing new bone erosions increased with younger age (adjusted odds ratio [aOR] 0.970; P < .001), higher Disease Activity Scores for 28 Joints-C-Reactive Protein (aOR per point increase 5.349; P < .001), presence of erosions at baseline (aOR 7.820; P < .001), and conventional DMARD-naive status (aOR 2.068; P  =  .033).

Study details: Findings are from a retrospective analysis of prospectively collected data of 578 patients with RA who started bDMARD treatment.

Disclosures: This study did not receive any funding. G Adami, D Gatti, and M Rossini declared receiving personal fees or serving as a consultant or speaker for various sources. The other authors declared no conflicts of interest.

Source: Adami G et al. Factors associated with radiographic progression in rheumatoid arthritis starting biological diseases modifying anti-rheumatic drugs (bDMARDs). Ther Adv Musculoskelet Dis. 2023;15:1759720X231174534 (Sep 28). doi: 10.1177/1759720X231174534

Key clinical point: Younger age, higher disease activity, prevalent erosions, and monotherapy were significant risk factors for the development of new bone erosions in biologic disease-modifying antirheumatic drug (bDMARD)-treated patients with rheumatoid arthritis (RA).

Major finding: Risk of developing new bone erosions increased with younger age (adjusted odds ratio [aOR] 0.970; P < .001), higher Disease Activity Scores for 28 Joints-C-Reactive Protein (aOR per point increase 5.349; P < .001), presence of erosions at baseline (aOR 7.820; P < .001), and conventional DMARD-naive status (aOR 2.068; P  =  .033).

Study details: Findings are from a retrospective analysis of prospectively collected data of 578 patients with RA who started bDMARD treatment.

Disclosures: This study did not receive any funding. G Adami, D Gatti, and M Rossini declared receiving personal fees or serving as a consultant or speaker for various sources. The other authors declared no conflicts of interest.

Source: Adami G et al. Factors associated with radiographic progression in rheumatoid arthritis starting biological diseases modifying anti-rheumatic drugs (bDMARDs). Ther Adv Musculoskelet Dis. 2023;15:1759720X231174534 (Sep 28). doi: 10.1177/1759720X231174534

Key clinical point: Younger age, higher disease activity, prevalent erosions, and monotherapy were significant risk factors for the development of new bone erosions in biologic disease-modifying antirheumatic drug (bDMARD)-treated patients with rheumatoid arthritis (RA).

Major finding: Risk of developing new bone erosions increased with younger age (adjusted odds ratio [aOR] 0.970; P < .001), higher Disease Activity Scores for 28 Joints-C-Reactive Protein (aOR per point increase 5.349; P < .001), presence of erosions at baseline (aOR 7.820; P < .001), and conventional DMARD-naive status (aOR 2.068; P  =  .033).

Study details: Findings are from a retrospective analysis of prospectively collected data of 578 patients with RA who started bDMARD treatment.

Disclosures: This study did not receive any funding. G Adami, D Gatti, and M Rossini declared receiving personal fees or serving as a consultant or speaker for various sources. The other authors declared no conflicts of interest.

Source: Adami G et al. Factors associated with radiographic progression in rheumatoid arthritis starting biological diseases modifying anti-rheumatic drugs (bDMARDs). Ther Adv Musculoskelet Dis. 2023;15:1759720X231174534 (Sep 28). doi: 10.1177/1759720X231174534