Key clinical point: Adolescent and young adult (AYA) patients with myelodysplastic syndrome (MDS) receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) generally exhibit better survival than their non-AYA counterparts.

Major finding: The 3-year overall survival (OS) in AYA patients was 71.2% (95% confidence interval, 67.4%-74.6%). Predictors of poor 3-year OS were active disease status (adjusted hazard ratio [aHR], 1.54; P = .016), poor cytogenetic risk (aHR, 1.62; P = .011), poor performance status (aHR, 2.01; P = .016), human leukocyte antigen (HLA)-matched unrelated donors (aHR, 2.23; P less than .001), HLA-mismatched unrelated donors (aHR, 2.16; P = .027), and cord blood transplantation (aHR, 2.44; P = 0.001).

Study details: The study included 645 AYA patients with MDS, aged 16-39 years, who received first allo-HSCT.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Source: Shimomura Y et al. Bone Marrow Transplant. 2021 May 15. doi: 10.1038/s41409-021-01324-8.

Key clinical point: Adolescent and young adult (AYA) patients with myelodysplastic syndrome (MDS) receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) generally exhibit better survival than their non-AYA counterparts.

Major finding: The 3-year overall survival (OS) in AYA patients was 71.2% (95% confidence interval, 67.4%-74.6%). Predictors of poor 3-year OS were active disease status (adjusted hazard ratio [aHR], 1.54; P = .016), poor cytogenetic risk (aHR, 1.62; P = .011), poor performance status (aHR, 2.01; P = .016), human leukocyte antigen (HLA)-matched unrelated donors (aHR, 2.23; P less than .001), HLA-mismatched unrelated donors (aHR, 2.16; P = .027), and cord blood transplantation (aHR, 2.44; P = 0.001).

Study details: The study included 645 AYA patients with MDS, aged 16-39 years, who received first allo-HSCT.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Source: Shimomura Y et al. Bone Marrow Transplant. 2021 May 15. doi: 10.1038/s41409-021-01324-8.

Key clinical point: Adolescent and young adult (AYA) patients with myelodysplastic syndrome (MDS) receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) generally exhibit better survival than their non-AYA counterparts.

Major finding: The 3-year overall survival (OS) in AYA patients was 71.2% (95% confidence interval, 67.4%-74.6%). Predictors of poor 3-year OS were active disease status (adjusted hazard ratio [aHR], 1.54; P = .016), poor cytogenetic risk (aHR, 1.62; P = .011), poor performance status (aHR, 2.01; P = .016), human leukocyte antigen (HLA)-matched unrelated donors (aHR, 2.23; P less than .001), HLA-mismatched unrelated donors (aHR, 2.16; P = .027), and cord blood transplantation (aHR, 2.44; P = 0.001).

Study details: The study included 645 AYA patients with MDS, aged 16-39 years, who received first allo-HSCT.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Source: Shimomura Y et al. Bone Marrow Transplant. 2021 May 15. doi: 10.1038/s41409-021-01324-8.

Key clinical point: Lenalidomide had no relevant effect on DNA methylation status in patients with myelodysplastic syndrome with isolated deletion of chromosome 5q (MDS del5q).

Major finding: Lenalidomide treatment did not have a relevant impact on genome-wide DNA methylation in patients with MDS del5q. However, methylation analysis before treatment could identify a distinct subgroup of patients (27%) with a trend toward inferior overall survival but not inferior progression-free survival.

Study details: DNA methylation analysis was performed on 51 MDS del5q patients treated with lenalidomide. Direct effects of lenalidomide on DNA methylation were studied using 17 paired samples pre- and posttreatment.

Disclosures: Open access funding by Projekt DEAL. This study was supported by funds from the Deutsche Forschungsgemeinschaft, “Deutsche Krebshilfe,” Gutermuth Foundation, H.W. & J. Hector fund, Baden Wuerttemberg, and Dr Rolf M Schwiete Fund. Mannheim DN is an endowed Professor of the German José-Carreras-Stiftung. The study was partly funded by a research grant from Celgene Inc.

Source: Hecht A et al. Ann Hematol. 2021 April 27. doi: 10.1007/s00277-021-04492-1.

Key clinical point: Lenalidomide had no relevant effect on DNA methylation status in patients with myelodysplastic syndrome with isolated deletion of chromosome 5q (MDS del5q).

Major finding: Lenalidomide treatment did not have a relevant impact on genome-wide DNA methylation in patients with MDS del5q. However, methylation analysis before treatment could identify a distinct subgroup of patients (27%) with a trend toward inferior overall survival but not inferior progression-free survival.

Study details: DNA methylation analysis was performed on 51 MDS del5q patients treated with lenalidomide. Direct effects of lenalidomide on DNA methylation were studied using 17 paired samples pre- and posttreatment.

Disclosures: Open access funding by Projekt DEAL. This study was supported by funds from the Deutsche Forschungsgemeinschaft, “Deutsche Krebshilfe,” Gutermuth Foundation, H.W. & J. Hector fund, Baden Wuerttemberg, and Dr Rolf M Schwiete Fund. Mannheim DN is an endowed Professor of the German José-Carreras-Stiftung. The study was partly funded by a research grant from Celgene Inc.

Source: Hecht A et al. Ann Hematol. 2021 April 27. doi: 10.1007/s00277-021-04492-1.

Key clinical point: Lenalidomide had no relevant effect on DNA methylation status in patients with myelodysplastic syndrome with isolated deletion of chromosome 5q (MDS del5q).

Major finding: Lenalidomide treatment did not have a relevant impact on genome-wide DNA methylation in patients with MDS del5q. However, methylation analysis before treatment could identify a distinct subgroup of patients (27%) with a trend toward inferior overall survival but not inferior progression-free survival.

Study details: DNA methylation analysis was performed on 51 MDS del5q patients treated with lenalidomide. Direct effects of lenalidomide on DNA methylation were studied using 17 paired samples pre- and posttreatment.

Disclosures: Open access funding by Projekt DEAL. This study was supported by funds from the Deutsche Forschungsgemeinschaft, “Deutsche Krebshilfe,” Gutermuth Foundation, H.W. & J. Hector fund, Baden Wuerttemberg, and Dr Rolf M Schwiete Fund. Mannheim DN is an endowed Professor of the German José-Carreras-Stiftung. The study was partly funded by a research grant from Celgene Inc.

Source: Hecht A et al. Ann Hematol. 2021 April 27. doi: 10.1007/s00277-021-04492-1.

Key clinical point: Pretransplant cytoreductive therapy is not associated with improved outcomes in patients with myelodysplastic syndromes (MDS) who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Major finding: Five-year overall survival after diagnosis was 73.6% (95% confidence interval [CI], 70.3%-76.9%), 43.4% (95% CI, 39.2%-47.6%), and 46.9% (95% CI, 44.7%-49.1%) in the upfront transplantation (upfront), induction chemotherapy (CT), and hypomethylating agents alone (HMA) groups, respectively (P = .033). Treatment-related mortality was 13.0% (95% CI, 11.4%-15.1%), 32.4% (95% CI, 30.1%-35.3%), and 28.4% (95% CI, 26.2%-30.3%) in the 3 groups, respectively (P = .028).

Study details: A total of 157 MDS patients were categorized into 3 groups based on the pretransplantation therapy: upfront (n=54), CT (n=66), and HMA (n=37). In addition, 124 patients underwent allo-HSCT.

Disclosures: This study was supported by the National Natural Science Foundation of China, Research and Development Program in Key Areas of Guangdong Province, Science and Technology Program of Guangzhou, and Clinical Research Start-up Project of Southern Medical University. The authors declared no conflicts of interest.

Source: Chen Y et al. Int J Cancer. 2021 Apr 25. doi: 10.1002/ijc.33608.

Key clinical point: Pretransplant cytoreductive therapy is not associated with improved outcomes in patients with myelodysplastic syndromes (MDS) who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Major finding: Five-year overall survival after diagnosis was 73.6% (95% confidence interval [CI], 70.3%-76.9%), 43.4% (95% CI, 39.2%-47.6%), and 46.9% (95% CI, 44.7%-49.1%) in the upfront transplantation (upfront), induction chemotherapy (CT), and hypomethylating agents alone (HMA) groups, respectively (P = .033). Treatment-related mortality was 13.0% (95% CI, 11.4%-15.1%), 32.4% (95% CI, 30.1%-35.3%), and 28.4% (95% CI, 26.2%-30.3%) in the 3 groups, respectively (P = .028).

Study details: A total of 157 MDS patients were categorized into 3 groups based on the pretransplantation therapy: upfront (n=54), CT (n=66), and HMA (n=37). In addition, 124 patients underwent allo-HSCT.

Disclosures: This study was supported by the National Natural Science Foundation of China, Research and Development Program in Key Areas of Guangdong Province, Science and Technology Program of Guangzhou, and Clinical Research Start-up Project of Southern Medical University. The authors declared no conflicts of interest.

Source: Chen Y et al. Int J Cancer. 2021 Apr 25. doi: 10.1002/ijc.33608.

Key clinical point: Pretransplant cytoreductive therapy is not associated with improved outcomes in patients with myelodysplastic syndromes (MDS) who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Major finding: Five-year overall survival after diagnosis was 73.6% (95% confidence interval [CI], 70.3%-76.9%), 43.4% (95% CI, 39.2%-47.6%), and 46.9% (95% CI, 44.7%-49.1%) in the upfront transplantation (upfront), induction chemotherapy (CT), and hypomethylating agents alone (HMA) groups, respectively (P = .033). Treatment-related mortality was 13.0% (95% CI, 11.4%-15.1%), 32.4% (95% CI, 30.1%-35.3%), and 28.4% (95% CI, 26.2%-30.3%) in the 3 groups, respectively (P = .028).

Study details: A total of 157 MDS patients were categorized into 3 groups based on the pretransplantation therapy: upfront (n=54), CT (n=66), and HMA (n=37). In addition, 124 patients underwent allo-HSCT.

Disclosures: This study was supported by the National Natural Science Foundation of China, Research and Development Program in Key Areas of Guangdong Province, Science and Technology Program of Guangzhou, and Clinical Research Start-up Project of Southern Medical University. The authors declared no conflicts of interest.

Source: Chen Y et al. Int J Cancer. 2021 Apr 25. doi: 10.1002/ijc.33608.

Case Report

A 67-year-old woman presented with a painful expanding ulcer on the left leg and a new nearby ulcer of 2 months’ duration. She initially was seen 2 months prior for a wound on the left knee due to a fall as well as cellulitis, which was treated with intravenous vancomycin and ceftriaxone. Wound cultures were negative for bacteria, and she was discharged without antibiotics. She presented to the emergency department 1 month later for malodorous discharge of the first ulcer with zero systemic inflammatory response syndrome criteria; no fever; and no abnormal heart rate, respiratory rate, or leukocyte count. She was discharged with wound care. After 3 weeks, she returned with a second ulcer and worsening drainage but zero systemic inflammatory response syndrome criteria. She had a medical history of Crohn disease with 9-year remission, atrial fibrillation, pacemaker, mitral valve replacement, chronic obstructive pulmonary disease, and a 51 pack-year smoking history.

Physical examination of the left leg revealed a 3×3-cm deep lesion (ulcer A) on the distal left thigh located superomedial to the knee (Figure 1) as well as a 2×1-cm deep lesion (ulcer B) on the anteromedial knee with undermining and tunneling (Figure 2). A large amount of malodorous tan bloody discharge was present on both ulcers. There were no signs of induration or crepitus.Due to concerns of skin and soft tissue infection (SSTI) or osteomyelitis, a bone scan and wound and blood cultures were ordered. The patient was started on vancomycin and piperacillin-tazobactam in the emergency department, which later was augmented with cefepime. Trauma surgery scheduled debridement for the following morning with suspicion of necrotizing fasciitis. Additional consultations were requested, including infectious disease, wound care, and dermatology. Dermatology evaluated the wound, performed a punch biopsy, and canceled debridement due to unclear diagnosis. The clinical differential at that time included pyoderma gangrenosum (PG), atypical vasculitis, or infection. Additional workup revealed positive antineutrophil cytoplasmic antibodies but negative proteinase 3 and myeloperoxidase, disfavoring vasculitis. Wound cultures grew Staphylococcus aureus and Pseudomonas aeruginosa.

Comment

Pyoderma gangrenosum is a rare inflammatory skin condition that classically presents as tender papules or pustules evolving into painful ulcers, most commonly on the lower extremities. Pyoderma gangrenosum has a propensity to exhibit pathergy, the hyperreactivity of the skin in response to minor trauma. This phenomenon in PG manifests as the rapid evolution from pustule to ulceration with violaceous undermining borders.

Diagnosis of PG
Pyoderma gangrenosum has been described as a diagnosis of exclusion, as its findings frequently mimic SSTIs. Important findings to obtain are histology, history, ulcer morphology, and response to treatment.

In 2018, Maverakis et al¹ proposed diagnostic criteria for classic ulcerative PG (Table 1). A diagnosis of PG can be made if the patient meets 1 major criterion and 4 minor criteria. Our case met 0 major criteria and 5 minor criteria: history of inflammatory bowel disease (IBD); history of pustule ulcerating within 4 days of appearing; peripheral erythema, undermining border, and tenderness at ulceration site; multiple ulcerations, with at least 1 on an anterior lower leg; and decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Although our patient’s biopsy demonstrated a mixed infiltrate, PG was not excluded due to spontaneous resolution at the time of biopsy, emphasizing the need to biopsy subsequent new lesions if neutrophils are not initially seen.¹ Pyoderma gangrenosum frequently is associated with IBD, most often Crohn disease, as seen in our patient.^2-4 Although IBD classically is associated with smoking, studies have yet to conclude if smoking is a predictive factor of PG.⁵ Our patient presented with an initial ulcer that evolved into 2 ulcers, similar to a case of bilateral ulcers.⁶

Management of PG
A gold standard of treatment of PG does not exist, but the goal is to promote wound healing. Patients with limited disease typically can be managed with wound care and topical steroids or calcineurin inhibitors, though data on efficacy are limited. However, our patient had more extensive disease and needed to be treated with systemic therapy. First-line therapy for extensive disease includes oral prednisone or cyclosporine for patients who cannot tolerate systemic corticosteroids.¹² Second-line and adjunctive therapy options include dapsone, minocycline, methotrexate, and infliximab. Our patient was prescribed a 7-month course of dapsone with outpatient dermatology and demonstrated resolution of both ulcers. Dapsone was tapered from a daily dose of 100 mg to 50 mg to 25 mg to none over the course of 2 to 3 months. Close monitoring with wound care is recommended, and petroleum jelly can be used for dry skin around the lesion for comfort.

Conclusion

The diagnosis of PG is challenging because it relies heavily on clinical signs and often mimics SSTI. Gathering a detailed medical history is critical to make the diagnosis of PG. In a patient with associated features of PG, dermatologic consultation and biopsy of skin lesions should be considered. Physicians should evaluate for suspected PG prior to proceeding with surgical intervention to avoid unnecessary amputation. The diagnostic criteria for classic ulcerative PG are gaining wider acceptance and are a useful tool for clinicians.

Case Report

A 67-year-old woman presented with a painful expanding ulcer on the left leg and a new nearby ulcer of 2 months’ duration. She initially was seen 2 months prior for a wound on the left knee due to a fall as well as cellulitis, which was treated with intravenous vancomycin and ceftriaxone. Wound cultures were negative for bacteria, and she was discharged without antibiotics. She presented to the emergency department 1 month later for malodorous discharge of the first ulcer with zero systemic inflammatory response syndrome criteria; no fever; and no abnormal heart rate, respiratory rate, or leukocyte count. She was discharged with wound care. After 3 weeks, she returned with a second ulcer and worsening drainage but zero systemic inflammatory response syndrome criteria. She had a medical history of Crohn disease with 9-year remission, atrial fibrillation, pacemaker, mitral valve replacement, chronic obstructive pulmonary disease, and a 51 pack-year smoking history.

Physical examination of the left leg revealed a 3×3-cm deep lesion (ulcer A) on the distal left thigh located superomedial to the knee (Figure 1) as well as a 2×1-cm deep lesion (ulcer B) on the anteromedial knee with undermining and tunneling (Figure 2). A large amount of malodorous tan bloody discharge was present on both ulcers. There were no signs of induration or crepitus.Due to concerns of skin and soft tissue infection (SSTI) or osteomyelitis, a bone scan and wound and blood cultures were ordered. The patient was started on vancomycin and piperacillin-tazobactam in the emergency department, which later was augmented with cefepime. Trauma surgery scheduled debridement for the following morning with suspicion of necrotizing fasciitis. Additional consultations were requested, including infectious disease, wound care, and dermatology. Dermatology evaluated the wound, performed a punch biopsy, and canceled debridement due to unclear diagnosis. The clinical differential at that time included pyoderma gangrenosum (PG), atypical vasculitis, or infection. Additional workup revealed positive antineutrophil cytoplasmic antibodies but negative proteinase 3 and myeloperoxidase, disfavoring vasculitis. Wound cultures grew Staphylococcus aureus and Pseudomonas aeruginosa.

Comment

Pyoderma gangrenosum is a rare inflammatory skin condition that classically presents as tender papules or pustules evolving into painful ulcers, most commonly on the lower extremities. Pyoderma gangrenosum has a propensity to exhibit pathergy, the hyperreactivity of the skin in response to minor trauma. This phenomenon in PG manifests as the rapid evolution from pustule to ulceration with violaceous undermining borders.

Diagnosis of PG
Pyoderma gangrenosum has been described as a diagnosis of exclusion, as its findings frequently mimic SSTIs. Important findings to obtain are histology, history, ulcer morphology, and response to treatment.

In 2018, Maverakis et al¹ proposed diagnostic criteria for classic ulcerative PG (Table 1). A diagnosis of PG can be made if the patient meets 1 major criterion and 4 minor criteria. Our case met 0 major criteria and 5 minor criteria: history of inflammatory bowel disease (IBD); history of pustule ulcerating within 4 days of appearing; peripheral erythema, undermining border, and tenderness at ulceration site; multiple ulcerations, with at least 1 on an anterior lower leg; and decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Although our patient’s biopsy demonstrated a mixed infiltrate, PG was not excluded due to spontaneous resolution at the time of biopsy, emphasizing the need to biopsy subsequent new lesions if neutrophils are not initially seen.¹ Pyoderma gangrenosum frequently is associated with IBD, most often Crohn disease, as seen in our patient.^2-4 Although IBD classically is associated with smoking, studies have yet to conclude if smoking is a predictive factor of PG.⁵ Our patient presented with an initial ulcer that evolved into 2 ulcers, similar to a case of bilateral ulcers.⁶

Management of PG
A gold standard of treatment of PG does not exist, but the goal is to promote wound healing. Patients with limited disease typically can be managed with wound care and topical steroids or calcineurin inhibitors, though data on efficacy are limited. However, our patient had more extensive disease and needed to be treated with systemic therapy. First-line therapy for extensive disease includes oral prednisone or cyclosporine for patients who cannot tolerate systemic corticosteroids.¹² Second-line and adjunctive therapy options include dapsone, minocycline, methotrexate, and infliximab. Our patient was prescribed a 7-month course of dapsone with outpatient dermatology and demonstrated resolution of both ulcers. Dapsone was tapered from a daily dose of 100 mg to 50 mg to 25 mg to none over the course of 2 to 3 months. Close monitoring with wound care is recommended, and petroleum jelly can be used for dry skin around the lesion for comfort.

Conclusion

The diagnosis of PG is challenging because it relies heavily on clinical signs and often mimics SSTI. Gathering a detailed medical history is critical to make the diagnosis of PG. In a patient with associated features of PG, dermatologic consultation and biopsy of skin lesions should be considered. Physicians should evaluate for suspected PG prior to proceeding with surgical intervention to avoid unnecessary amputation. The diagnostic criteria for classic ulcerative PG are gaining wider acceptance and are a useful tool for clinicians.

Case Report

A 67-year-old woman presented with a painful expanding ulcer on the left leg and a new nearby ulcer of 2 months’ duration. She initially was seen 2 months prior for a wound on the left knee due to a fall as well as cellulitis, which was treated with intravenous vancomycin and ceftriaxone. Wound cultures were negative for bacteria, and she was discharged without antibiotics. She presented to the emergency department 1 month later for malodorous discharge of the first ulcer with zero systemic inflammatory response syndrome criteria; no fever; and no abnormal heart rate, respiratory rate, or leukocyte count. She was discharged with wound care. After 3 weeks, she returned with a second ulcer and worsening drainage but zero systemic inflammatory response syndrome criteria. She had a medical history of Crohn disease with 9-year remission, atrial fibrillation, pacemaker, mitral valve replacement, chronic obstructive pulmonary disease, and a 51 pack-year smoking history.

Physical examination of the left leg revealed a 3×3-cm deep lesion (ulcer A) on the distal left thigh located superomedial to the knee (Figure 1) as well as a 2×1-cm deep lesion (ulcer B) on the anteromedial knee with undermining and tunneling (Figure 2). A large amount of malodorous tan bloody discharge was present on both ulcers. There were no signs of induration or crepitus.Due to concerns of skin and soft tissue infection (SSTI) or osteomyelitis, a bone scan and wound and blood cultures were ordered. The patient was started on vancomycin and piperacillin-tazobactam in the emergency department, which later was augmented with cefepime. Trauma surgery scheduled debridement for the following morning with suspicion of necrotizing fasciitis. Additional consultations were requested, including infectious disease, wound care, and dermatology. Dermatology evaluated the wound, performed a punch biopsy, and canceled debridement due to unclear diagnosis. The clinical differential at that time included pyoderma gangrenosum (PG), atypical vasculitis, or infection. Additional workup revealed positive antineutrophil cytoplasmic antibodies but negative proteinase 3 and myeloperoxidase, disfavoring vasculitis. Wound cultures grew Staphylococcus aureus and Pseudomonas aeruginosa.

Comment

Pyoderma gangrenosum is a rare inflammatory skin condition that classically presents as tender papules or pustules evolving into painful ulcers, most commonly on the lower extremities. Pyoderma gangrenosum has a propensity to exhibit pathergy, the hyperreactivity of the skin in response to minor trauma. This phenomenon in PG manifests as the rapid evolution from pustule to ulceration with violaceous undermining borders.

Diagnosis of PG
Pyoderma gangrenosum has been described as a diagnosis of exclusion, as its findings frequently mimic SSTIs. Important findings to obtain are histology, history, ulcer morphology, and response to treatment.

In 2018, Maverakis et al¹ proposed diagnostic criteria for classic ulcerative PG (Table 1). A diagnosis of PG can be made if the patient meets 1 major criterion and 4 minor criteria. Our case met 0 major criteria and 5 minor criteria: history of inflammatory bowel disease (IBD); history of pustule ulcerating within 4 days of appearing; peripheral erythema, undermining border, and tenderness at ulceration site; multiple ulcerations, with at least 1 on an anterior lower leg; and decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Although our patient’s biopsy demonstrated a mixed infiltrate, PG was not excluded due to spontaneous resolution at the time of biopsy, emphasizing the need to biopsy subsequent new lesions if neutrophils are not initially seen.¹ Pyoderma gangrenosum frequently is associated with IBD, most often Crohn disease, as seen in our patient.^2-4 Although IBD classically is associated with smoking, studies have yet to conclude if smoking is a predictive factor of PG.⁵ Our patient presented with an initial ulcer that evolved into 2 ulcers, similar to a case of bilateral ulcers.⁶

Management of PG
A gold standard of treatment of PG does not exist, but the goal is to promote wound healing. Patients with limited disease typically can be managed with wound care and topical steroids or calcineurin inhibitors, though data on efficacy are limited. However, our patient had more extensive disease and needed to be treated with systemic therapy. First-line therapy for extensive disease includes oral prednisone or cyclosporine for patients who cannot tolerate systemic corticosteroids.¹² Second-line and adjunctive therapy options include dapsone, minocycline, methotrexate, and infliximab. Our patient was prescribed a 7-month course of dapsone with outpatient dermatology and demonstrated resolution of both ulcers. Dapsone was tapered from a daily dose of 100 mg to 50 mg to 25 mg to none over the course of 2 to 3 months. Close monitoring with wound care is recommended, and petroleum jelly can be used for dry skin around the lesion for comfort.

Conclusion

The diagnosis of PG is challenging because it relies heavily on clinical signs and often mimics SSTI. Gathering a detailed medical history is critical to make the diagnosis of PG. In a patient with associated features of PG, dermatologic consultation and biopsy of skin lesions should be considered. Physicians should evaluate for suspected PG prior to proceeding with surgical intervention to avoid unnecessary amputation. The diagnostic criteria for classic ulcerative PG are gaining wider acceptance and are a useful tool for clinicians.

Key clinical point: In patients with very high-risk TP53-mutated myelodysplastic syndromes (MDS), addition of eprenetapopt to azacitidine (AZA) was safe and led to better clinical outcomes than AZA alone.

Major finding: The overall response rate in MDS patients was 62% including 47% complete remission. The median duration of response in MDS patients was 10.4 months. At a median follow-up of 9.7 months, the median overall survival in MDS patients was 12.1 months. Eprenetapopt plus AZA was generally well tolerated.

Study details: Phase 2 study of eprenetapopt plus AZA vs. AZA alone in 34 very high-risk TP53-mutated MDS patients.

Disclosures: The study was supported by Groupe Francophone des Myelodysplasies. The authors reported relationships with various pharmaceutical companies.

Source: Cluzeau T et al. J Clin Oncol. 2021 Feb 18. doi: 10.1200/JCO.20.02342.

Key clinical point: In patients with very high-risk TP53-mutated myelodysplastic syndromes (MDS), addition of eprenetapopt to azacitidine (AZA) was safe and led to better clinical outcomes than AZA alone.

Major finding: The overall response rate in MDS patients was 62% including 47% complete remission. The median duration of response in MDS patients was 10.4 months. At a median follow-up of 9.7 months, the median overall survival in MDS patients was 12.1 months. Eprenetapopt plus AZA was generally well tolerated.

Study details: Phase 2 study of eprenetapopt plus AZA vs. AZA alone in 34 very high-risk TP53-mutated MDS patients.

Disclosures: The study was supported by Groupe Francophone des Myelodysplasies. The authors reported relationships with various pharmaceutical companies.

Source: Cluzeau T et al. J Clin Oncol. 2021 Feb 18. doi: 10.1200/JCO.20.02342.

Key clinical point: In patients with very high-risk TP53-mutated myelodysplastic syndromes (MDS), addition of eprenetapopt to azacitidine (AZA) was safe and led to better clinical outcomes than AZA alone.

Major finding: The overall response rate in MDS patients was 62% including 47% complete remission. The median duration of response in MDS patients was 10.4 months. At a median follow-up of 9.7 months, the median overall survival in MDS patients was 12.1 months. Eprenetapopt plus AZA was generally well tolerated.

Study details: Phase 2 study of eprenetapopt plus AZA vs. AZA alone in 34 very high-risk TP53-mutated MDS patients.

Disclosures: The study was supported by Groupe Francophone des Myelodysplasies. The authors reported relationships with various pharmaceutical companies.

Source: Cluzeau T et al. J Clin Oncol. 2021 Feb 18. doi: 10.1200/JCO.20.02342.

Allogeneic stem cell transplantation (SCT) remains the only potential curable option for patients with myelodysplastic syndromes (MDS). While MDS mainly occurs in older patients, MDS does occur in younger patients and prior studies have suggested better overall survival (OS) for younger patients undergoing allogeneic SCT.  Shimomura et al (BMT 2021) analyzed the outcome of 645 patients aged 16-39 years old who received allogeneic SCT in Japan. In this multicenter retrospective analysis, 3 year OS was 71%. In the cohort, 37% of patients had either intermediate-2 or high risk by IPSS, 41% had active disease prior to SCT, and 10% had secondary MDS.  In a multivariate analysis, active disease status, poor cytogenetic risk, and transplant other than from related donor were associated with poor 3 year OS. Cumulative 3 year relapse was 11% and 3 year non-relapse mortality was 19%, which is lower than those of older patients with MDS which ranges from 30-40%. Limitations from this analysis are lack of genetic mutation data, as well as lack of incorporation of prior MDS directed therapy with outcome analysis, however this analysis from a large retrospective cohort provides valuable information regarding outcome in young patients with MDS.

Use of melphalan in multiple myeloma is associated with increased risk of developing MDS and acute myeloid leukemia (AML).  Jonsdottir et al (European Journal of Hematology) reported results of a large population-based study using the Swedish cancer registry to determine relationship of exposure to melphalan treatment for multiple myeloma and development of subsequent MDS and AML. Out of 26,627 patients with multiple myeloma in the Swedish cancer registry, 0.5% (124) patients developed subsequent MDS or AML. The median time from multiple myeloma diagnosis to MDS or AML diagnosis was 3.8 years. There was about threefold higher cumulative exposure to melphalan among those who developed MDS or AML compared to those who did not develop MDS or AML (OR=2.8, 95% CI 1.7-5.2, P < 0.001). There was no difference among the groups in exposure and dosing of radiation therapy, cumulative dose of cyclophosphamide, or doxorubicine. This large population-based study confirms the association between melphalan therapy and development of MDS/AML.

Febrile neutropenia is a common complication for neutropenic patients undergoing therapy. Patients who develop febrile neutropenia are treated with empiric broad-spectrum antibiotics, however there is conflicting recommended duration of antimicrobial treatment in absence of evidence of bacterial infection. The Infectious Disease Society of America recommends antibiotic treatment until marrow recovery, while the European Conference of Infections in Leukemia guidelines suggest consideration of discontinuation after 72 hours if the patient is hemodynamically stable and afebrile for 48 hours. Schauwvlieghe et al (EClinical Medicine 2021) compared the outcome of MDS and AML patients with febrile neutropenia during induction chemotherapy receiving a shortened 3 day empiric antibiotic therapy in absence of documented infection to those receiving antibiotics until neutrophil recovery in a retrospective comparative cohort study in two hospitals in the HOVON network. The shorted antibiotic group received a median of 9 days of antibiotics, compared to 19 days. The primary endpoint was the rate of serious medical complications; there was no statistical difference between the two groups (12.5% for shortened antibiotics vs 8.9% for prolonged antibiotics, P = 0.17).  There was no difference in serious medical complications when adjusting for age, AML risk, non-pulmonary HCT-CI score, and year of admission. There was also no significant difference in infection-related 30-day mortality among the two groups. This study suggests that for patients who develop febrile neutropenia while receiving induction chemotherapy, it may be safe to consider stopping antibiotics after 3 days in absence of infection. A prospective trial should be considered to further evaluate the safety of shortened antibiotic course.

Allogeneic stem cell transplantation (SCT) remains the only potential curable option for patients with myelodysplastic syndromes (MDS). While MDS mainly occurs in older patients, MDS does occur in younger patients and prior studies have suggested better overall survival (OS) for younger patients undergoing allogeneic SCT.  Shimomura et al (BMT 2021) analyzed the outcome of 645 patients aged 16-39 years old who received allogeneic SCT in Japan. In this multicenter retrospective analysis, 3 year OS was 71%. In the cohort, 37% of patients had either intermediate-2 or high risk by IPSS, 41% had active disease prior to SCT, and 10% had secondary MDS.  In a multivariate analysis, active disease status, poor cytogenetic risk, and transplant other than from related donor were associated with poor 3 year OS. Cumulative 3 year relapse was 11% and 3 year non-relapse mortality was 19%, which is lower than those of older patients with MDS which ranges from 30-40%. Limitations from this analysis are lack of genetic mutation data, as well as lack of incorporation of prior MDS directed therapy with outcome analysis, however this analysis from a large retrospective cohort provides valuable information regarding outcome in young patients with MDS.

Use of melphalan in multiple myeloma is associated with increased risk of developing MDS and acute myeloid leukemia (AML).  Jonsdottir et al (European Journal of Hematology) reported results of a large population-based study using the Swedish cancer registry to determine relationship of exposure to melphalan treatment for multiple myeloma and development of subsequent MDS and AML. Out of 26,627 patients with multiple myeloma in the Swedish cancer registry, 0.5% (124) patients developed subsequent MDS or AML. The median time from multiple myeloma diagnosis to MDS or AML diagnosis was 3.8 years. There was about threefold higher cumulative exposure to melphalan among those who developed MDS or AML compared to those who did not develop MDS or AML (OR=2.8, 95% CI 1.7-5.2, P < 0.001). There was no difference among the groups in exposure and dosing of radiation therapy, cumulative dose of cyclophosphamide, or doxorubicine. This large population-based study confirms the association between melphalan therapy and development of MDS/AML.

Febrile neutropenia is a common complication for neutropenic patients undergoing therapy. Patients who develop febrile neutropenia are treated with empiric broad-spectrum antibiotics, however there is conflicting recommended duration of antimicrobial treatment in absence of evidence of bacterial infection. The Infectious Disease Society of America recommends antibiotic treatment until marrow recovery, while the European Conference of Infections in Leukemia guidelines suggest consideration of discontinuation after 72 hours if the patient is hemodynamically stable and afebrile for 48 hours. Schauwvlieghe et al (EClinical Medicine 2021) compared the outcome of MDS and AML patients with febrile neutropenia during induction chemotherapy receiving a shortened 3 day empiric antibiotic therapy in absence of documented infection to those receiving antibiotics until neutrophil recovery in a retrospective comparative cohort study in two hospitals in the HOVON network. The shorted antibiotic group received a median of 9 days of antibiotics, compared to 19 days. The primary endpoint was the rate of serious medical complications; there was no statistical difference between the two groups (12.5% for shortened antibiotics vs 8.9% for prolonged antibiotics, P = 0.17).  There was no difference in serious medical complications when adjusting for age, AML risk, non-pulmonary HCT-CI score, and year of admission. There was also no significant difference in infection-related 30-day mortality among the two groups. This study suggests that for patients who develop febrile neutropenia while receiving induction chemotherapy, it may be safe to consider stopping antibiotics after 3 days in absence of infection. A prospective trial should be considered to further evaluate the safety of shortened antibiotic course.

Allogeneic stem cell transplantation (SCT) remains the only potential curable option for patients with myelodysplastic syndromes (MDS). While MDS mainly occurs in older patients, MDS does occur in younger patients and prior studies have suggested better overall survival (OS) for younger patients undergoing allogeneic SCT.  Shimomura et al (BMT 2021) analyzed the outcome of 645 patients aged 16-39 years old who received allogeneic SCT in Japan. In this multicenter retrospective analysis, 3 year OS was 71%. In the cohort, 37% of patients had either intermediate-2 or high risk by IPSS, 41% had active disease prior to SCT, and 10% had secondary MDS.  In a multivariate analysis, active disease status, poor cytogenetic risk, and transplant other than from related donor were associated with poor 3 year OS. Cumulative 3 year relapse was 11% and 3 year non-relapse mortality was 19%, which is lower than those of older patients with MDS which ranges from 30-40%. Limitations from this analysis are lack of genetic mutation data, as well as lack of incorporation of prior MDS directed therapy with outcome analysis, however this analysis from a large retrospective cohort provides valuable information regarding outcome in young patients with MDS.

Use of melphalan in multiple myeloma is associated with increased risk of developing MDS and acute myeloid leukemia (AML).  Jonsdottir et al (European Journal of Hematology) reported results of a large population-based study using the Swedish cancer registry to determine relationship of exposure to melphalan treatment for multiple myeloma and development of subsequent MDS and AML. Out of 26,627 patients with multiple myeloma in the Swedish cancer registry, 0.5% (124) patients developed subsequent MDS or AML. The median time from multiple myeloma diagnosis to MDS or AML diagnosis was 3.8 years. There was about threefold higher cumulative exposure to melphalan among those who developed MDS or AML compared to those who did not develop MDS or AML (OR=2.8, 95% CI 1.7-5.2, P < 0.001). There was no difference among the groups in exposure and dosing of radiation therapy, cumulative dose of cyclophosphamide, or doxorubicine. This large population-based study confirms the association between melphalan therapy and development of MDS/AML.

Febrile neutropenia is a common complication for neutropenic patients undergoing therapy. Patients who develop febrile neutropenia are treated with empiric broad-spectrum antibiotics, however there is conflicting recommended duration of antimicrobial treatment in absence of evidence of bacterial infection. The Infectious Disease Society of America recommends antibiotic treatment until marrow recovery, while the European Conference of Infections in Leukemia guidelines suggest consideration of discontinuation after 72 hours if the patient is hemodynamically stable and afebrile for 48 hours. Schauwvlieghe et al (EClinical Medicine 2021) compared the outcome of MDS and AML patients with febrile neutropenia during induction chemotherapy receiving a shortened 3 day empiric antibiotic therapy in absence of documented infection to those receiving antibiotics until neutrophil recovery in a retrospective comparative cohort study in two hospitals in the HOVON network. The shorted antibiotic group received a median of 9 days of antibiotics, compared to 19 days. The primary endpoint was the rate of serious medical complications; there was no statistical difference between the two groups (12.5% for shortened antibiotics vs 8.9% for prolonged antibiotics, P = 0.17).  There was no difference in serious medical complications when adjusting for age, AML risk, non-pulmonary HCT-CI score, and year of admission. There was also no significant difference in infection-related 30-day mortality among the two groups. This study suggests that for patients who develop febrile neutropenia while receiving induction chemotherapy, it may be safe to consider stopping antibiotics after 3 days in absence of infection. A prospective trial should be considered to further evaluate the safety of shortened antibiotic course.

Patients with rheumatoid arthritis who were using rituximab at the time of COVID-19 onset had a fourfold higher risk of being hospitalized, needing mechanical ventilation, or dying, compared with patients taking a tumor necrosis factor inhibitor (TNFi), according to a report given at the annual European Congress of Rheumatology.

The use of Janus kinase inhibitors (JAKi) also was associated with a twofold higher risk for these COVID-19 outcomes, said Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in presenting the analysis from the COVID-19 Global Rheumatology Alliance (GRA) Physician Registry.

“The strong association of rituximab and JAK inhibitor use with poor COVID-19 outcomes highlights the prioritization of risk mitigation strategies for these patients,” Dr. Sparks said at the meeting.

The full findings have now been published in Annals of the Rheumatic Diseases.
 

JAKi association questioned

These findings provide “an important understanding for the risk of our patients in times before vaccination,” said Hendrik Schulze-Koops, MD, of Ludwig Maximilian University of Munich, who chaired the session in which the study was presented.

However, “recently, baricitinib was licensed to prevent particular aspects of severe COVID. What’s the explanation for this discrepancy?” he asked.

“Certainly, the JAK inhibitor finding deserves further study,” Dr. Sparks acknowledged, adding that the data were analyzed by class rather than for individual drugs.

“One possible explanation could be when JAK inhibitors are used,” he suggested. “It might be different for patients who [have been] just infected – that might have different biologic effects – as opposed to choosing to treat patients right when there’s a hyperinflammatory cascade, or there’s oxygen need.”

Regarding the JAK inhibitor finding, Ronald van Vollenhoven, MD, PhD, of the University of Amsterdam, pointed out during the online Q&A that “JAKi have a very short half-life compared to biologics.”

Dr. van Vollenhoven asked: “Could the practice of stopping these drugs upon COVID infection have a negative impact on the course?” To which Dr. Sparks responded: “The different half-life of drugs would be a promising avenue to look at, to see whether increases in disease activity might have imparted some of the effects we saw.”
 

Performing the analysis

As of April 12, 2021, the GRA Physician Registry contained the records of more than 15,000 patients. Dr. Sparks, collaborator Zachary Wallace, MD, of Massachusetts General Hospital, Boston, and associates limited their analysis to 2,869 patients with RA who had been treated with either a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) at the time they were diagnosed with COVID-19.

“We wanted to limit it to a single disease and also limit it to drugs that are considered for that disease,” Dr. Sparks explained in an interview.

“Because patients with rheumatoid arthritis are often treated sequentially, we wanted to further limit the analysis to patients who were on advanced therapies so that they were at a similar disease state, and also had the opportunity to receive advanced therapies.”

This approach hopefully minimizes the possibility of confounding by indication, Dr. Sparks said.

Most of the patients included in the analysis had received a TNFi (n = 1,388), and they were used as the control arm of the analysis. Outcomes associated with treatment with the other b/tsDMARDs, which included abatacept (n = 237), rituximab (n = 364), interleukin-6 inhibitors (IL-6i; n = 317), and JAKi (n = 563), were then compared with TNFi.

Baseline characteristics of patients were broadly similar across the groups. The mean age was 56.7 years and 80.8% of the study population was female. There were a few expected differences among users of rituximab versus TNFi, notably a higher percentage of patients with interstitial lung disease (11% vs. 1.4% of TNFi users) or cancer (7.4% vs. 0.9%) among patients treated with rituximab since it is commonly used in these patients, Dr. Sparks said.

“We did perform a sensitivity analysis where we restricted the population to not having ILD or cancer and we actually found really similar findings,” he added.

Four COVID-19 outcomes assessed

The researchers used a four-point ordinal scale modeled after one set by the World Health Organization to assess four COVID-19 outcomes: not hospitalized, hospitalized without oxygenation, hospitalized with oxygenation or ventilation, and death.

Odds ratios (ORs) comparing rituximab to TNFi for these four COVID-19 outcomes were a respective 4.53, 2.87, 4.05, and 4.57. The ORs for JAKi versus TNFi were a respective 2.4, 1.55, 2.03, and 2.04.

“We found no consistent associations of abatacept or interleukin-6 inhibitors with COVID-19 severity, compared to TNF inhibitors,” which is reassuring, Dr. Sparks said.

ORs for the four COVID-19 outcomes with abatacept were a respective 1.18, 1.12, 1.41, and 1.46, and for IL-6i were 0.84, 0.72, 0.75, and 1.13.

Rituximab use in patients with RA who develop COVID-19

So, should rituximab be stopped in patients with RA if they develop COVID-19? “This is an important question and one that would be decided on a case-by-case basis,” Dr. Sparks said. “Of course, the drug has a very long half-life, so risk mitigation strategies are still of utmost importance,” he added.

“I think everyone’s a bit reticent to want to start rituximab in this environment, but it might also make me pause about starting a JAK inhibitor,” Dr. Sparks added. “Given that this is a first finding, I’m not sure I would necessarily change patients who are doing well on these medications. I think what it really makes me want to do is to try to obviously vaccinate the patients on JAK inhibitors as they do have a short half-life.”

More observational studies would be helpful, Dr. Sparks said, adding that “the most pressing need is to try to figure out how to protect our patients with rituximab.”

The COVID-19 Global Rheumatology Alliance Physician Registry is supported by the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Dr. Sparks disclosed serving as a consultant for Bristol Myers Squibb, Gilead, Inova, Optum, and Pfizer for work unrelated to this study. Dr. Wallace disclosed receiving grant support from Bristol Myers Squibb and Principia/Sanofi and serving as a consultant for Viela Bio and Medpace for work unrelated to this study.

Patients with rheumatoid arthritis who were using rituximab at the time of COVID-19 onset had a fourfold higher risk of being hospitalized, needing mechanical ventilation, or dying, compared with patients taking a tumor necrosis factor inhibitor (TNFi), according to a report given at the annual European Congress of Rheumatology.

The use of Janus kinase inhibitors (JAKi) also was associated with a twofold higher risk for these COVID-19 outcomes, said Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in presenting the analysis from the COVID-19 Global Rheumatology Alliance (GRA) Physician Registry.

“The strong association of rituximab and JAK inhibitor use with poor COVID-19 outcomes highlights the prioritization of risk mitigation strategies for these patients,” Dr. Sparks said at the meeting.

The full findings have now been published in Annals of the Rheumatic Diseases.
 

JAKi association questioned

These findings provide “an important understanding for the risk of our patients in times before vaccination,” said Hendrik Schulze-Koops, MD, of Ludwig Maximilian University of Munich, who chaired the session in which the study was presented.

However, “recently, baricitinib was licensed to prevent particular aspects of severe COVID. What’s the explanation for this discrepancy?” he asked.

“Certainly, the JAK inhibitor finding deserves further study,” Dr. Sparks acknowledged, adding that the data were analyzed by class rather than for individual drugs.

“One possible explanation could be when JAK inhibitors are used,” he suggested. “It might be different for patients who [have been] just infected – that might have different biologic effects – as opposed to choosing to treat patients right when there’s a hyperinflammatory cascade, or there’s oxygen need.”

Regarding the JAK inhibitor finding, Ronald van Vollenhoven, MD, PhD, of the University of Amsterdam, pointed out during the online Q&A that “JAKi have a very short half-life compared to biologics.”

Dr. van Vollenhoven asked: “Could the practice of stopping these drugs upon COVID infection have a negative impact on the course?” To which Dr. Sparks responded: “The different half-life of drugs would be a promising avenue to look at, to see whether increases in disease activity might have imparted some of the effects we saw.”
 

Performing the analysis

As of April 12, 2021, the GRA Physician Registry contained the records of more than 15,000 patients. Dr. Sparks, collaborator Zachary Wallace, MD, of Massachusetts General Hospital, Boston, and associates limited their analysis to 2,869 patients with RA who had been treated with either a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) at the time they were diagnosed with COVID-19.

“We wanted to limit it to a single disease and also limit it to drugs that are considered for that disease,” Dr. Sparks explained in an interview.

“Because patients with rheumatoid arthritis are often treated sequentially, we wanted to further limit the analysis to patients who were on advanced therapies so that they were at a similar disease state, and also had the opportunity to receive advanced therapies.”

This approach hopefully minimizes the possibility of confounding by indication, Dr. Sparks said.

Most of the patients included in the analysis had received a TNFi (n = 1,388), and they were used as the control arm of the analysis. Outcomes associated with treatment with the other b/tsDMARDs, which included abatacept (n = 237), rituximab (n = 364), interleukin-6 inhibitors (IL-6i; n = 317), and JAKi (n = 563), were then compared with TNFi.

Baseline characteristics of patients were broadly similar across the groups. The mean age was 56.7 years and 80.8% of the study population was female. There were a few expected differences among users of rituximab versus TNFi, notably a higher percentage of patients with interstitial lung disease (11% vs. 1.4% of TNFi users) or cancer (7.4% vs. 0.9%) among patients treated with rituximab since it is commonly used in these patients, Dr. Sparks said.

“We did perform a sensitivity analysis where we restricted the population to not having ILD or cancer and we actually found really similar findings,” he added.

Four COVID-19 outcomes assessed

The researchers used a four-point ordinal scale modeled after one set by the World Health Organization to assess four COVID-19 outcomes: not hospitalized, hospitalized without oxygenation, hospitalized with oxygenation or ventilation, and death.

Odds ratios (ORs) comparing rituximab to TNFi for these four COVID-19 outcomes were a respective 4.53, 2.87, 4.05, and 4.57. The ORs for JAKi versus TNFi were a respective 2.4, 1.55, 2.03, and 2.04.

“We found no consistent associations of abatacept or interleukin-6 inhibitors with COVID-19 severity, compared to TNF inhibitors,” which is reassuring, Dr. Sparks said.

ORs for the four COVID-19 outcomes with abatacept were a respective 1.18, 1.12, 1.41, and 1.46, and for IL-6i were 0.84, 0.72, 0.75, and 1.13.

Rituximab use in patients with RA who develop COVID-19

So, should rituximab be stopped in patients with RA if they develop COVID-19? “This is an important question and one that would be decided on a case-by-case basis,” Dr. Sparks said. “Of course, the drug has a very long half-life, so risk mitigation strategies are still of utmost importance,” he added.

“I think everyone’s a bit reticent to want to start rituximab in this environment, but it might also make me pause about starting a JAK inhibitor,” Dr. Sparks added. “Given that this is a first finding, I’m not sure I would necessarily change patients who are doing well on these medications. I think what it really makes me want to do is to try to obviously vaccinate the patients on JAK inhibitors as they do have a short half-life.”

More observational studies would be helpful, Dr. Sparks said, adding that “the most pressing need is to try to figure out how to protect our patients with rituximab.”

The COVID-19 Global Rheumatology Alliance Physician Registry is supported by the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Dr. Sparks disclosed serving as a consultant for Bristol Myers Squibb, Gilead, Inova, Optum, and Pfizer for work unrelated to this study. Dr. Wallace disclosed receiving grant support from Bristol Myers Squibb and Principia/Sanofi and serving as a consultant for Viela Bio and Medpace for work unrelated to this study.

Patients with rheumatoid arthritis who were using rituximab at the time of COVID-19 onset had a fourfold higher risk of being hospitalized, needing mechanical ventilation, or dying, compared with patients taking a tumor necrosis factor inhibitor (TNFi), according to a report given at the annual European Congress of Rheumatology.

The use of Janus kinase inhibitors (JAKi) also was associated with a twofold higher risk for these COVID-19 outcomes, said Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in presenting the analysis from the COVID-19 Global Rheumatology Alliance (GRA) Physician Registry.

“The strong association of rituximab and JAK inhibitor use with poor COVID-19 outcomes highlights the prioritization of risk mitigation strategies for these patients,” Dr. Sparks said at the meeting.

The full findings have now been published in Annals of the Rheumatic Diseases.
 

JAKi association questioned

These findings provide “an important understanding for the risk of our patients in times before vaccination,” said Hendrik Schulze-Koops, MD, of Ludwig Maximilian University of Munich, who chaired the session in which the study was presented.

However, “recently, baricitinib was licensed to prevent particular aspects of severe COVID. What’s the explanation for this discrepancy?” he asked.

“Certainly, the JAK inhibitor finding deserves further study,” Dr. Sparks acknowledged, adding that the data were analyzed by class rather than for individual drugs.

“One possible explanation could be when JAK inhibitors are used,” he suggested. “It might be different for patients who [have been] just infected – that might have different biologic effects – as opposed to choosing to treat patients right when there’s a hyperinflammatory cascade, or there’s oxygen need.”

Regarding the JAK inhibitor finding, Ronald van Vollenhoven, MD, PhD, of the University of Amsterdam, pointed out during the online Q&A that “JAKi have a very short half-life compared to biologics.”

Dr. van Vollenhoven asked: “Could the practice of stopping these drugs upon COVID infection have a negative impact on the course?” To which Dr. Sparks responded: “The different half-life of drugs would be a promising avenue to look at, to see whether increases in disease activity might have imparted some of the effects we saw.”
 

Performing the analysis

As of April 12, 2021, the GRA Physician Registry contained the records of more than 15,000 patients. Dr. Sparks, collaborator Zachary Wallace, MD, of Massachusetts General Hospital, Boston, and associates limited their analysis to 2,869 patients with RA who had been treated with either a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) at the time they were diagnosed with COVID-19.

“We wanted to limit it to a single disease and also limit it to drugs that are considered for that disease,” Dr. Sparks explained in an interview.

“Because patients with rheumatoid arthritis are often treated sequentially, we wanted to further limit the analysis to patients who were on advanced therapies so that they were at a similar disease state, and also had the opportunity to receive advanced therapies.”

This approach hopefully minimizes the possibility of confounding by indication, Dr. Sparks said.

Most of the patients included in the analysis had received a TNFi (n = 1,388), and they were used as the control arm of the analysis. Outcomes associated with treatment with the other b/tsDMARDs, which included abatacept (n = 237), rituximab (n = 364), interleukin-6 inhibitors (IL-6i; n = 317), and JAKi (n = 563), were then compared with TNFi.

Baseline characteristics of patients were broadly similar across the groups. The mean age was 56.7 years and 80.8% of the study population was female. There were a few expected differences among users of rituximab versus TNFi, notably a higher percentage of patients with interstitial lung disease (11% vs. 1.4% of TNFi users) or cancer (7.4% vs. 0.9%) among patients treated with rituximab since it is commonly used in these patients, Dr. Sparks said.

“We did perform a sensitivity analysis where we restricted the population to not having ILD or cancer and we actually found really similar findings,” he added.

Four COVID-19 outcomes assessed

The researchers used a four-point ordinal scale modeled after one set by the World Health Organization to assess four COVID-19 outcomes: not hospitalized, hospitalized without oxygenation, hospitalized with oxygenation or ventilation, and death.

Odds ratios (ORs) comparing rituximab to TNFi for these four COVID-19 outcomes were a respective 4.53, 2.87, 4.05, and 4.57. The ORs for JAKi versus TNFi were a respective 2.4, 1.55, 2.03, and 2.04.

“We found no consistent associations of abatacept or interleukin-6 inhibitors with COVID-19 severity, compared to TNF inhibitors,” which is reassuring, Dr. Sparks said.

ORs for the four COVID-19 outcomes with abatacept were a respective 1.18, 1.12, 1.41, and 1.46, and for IL-6i were 0.84, 0.72, 0.75, and 1.13.

Rituximab use in patients with RA who develop COVID-19

So, should rituximab be stopped in patients with RA if they develop COVID-19? “This is an important question and one that would be decided on a case-by-case basis,” Dr. Sparks said. “Of course, the drug has a very long half-life, so risk mitigation strategies are still of utmost importance,” he added.

“I think everyone’s a bit reticent to want to start rituximab in this environment, but it might also make me pause about starting a JAK inhibitor,” Dr. Sparks added. “Given that this is a first finding, I’m not sure I would necessarily change patients who are doing well on these medications. I think what it really makes me want to do is to try to obviously vaccinate the patients on JAK inhibitors as they do have a short half-life.”

More observational studies would be helpful, Dr. Sparks said, adding that “the most pressing need is to try to figure out how to protect our patients with rituximab.”

The COVID-19 Global Rheumatology Alliance Physician Registry is supported by the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Dr. Sparks disclosed serving as a consultant for Bristol Myers Squibb, Gilead, Inova, Optum, and Pfizer for work unrelated to this study. Dr. Wallace disclosed receiving grant support from Bristol Myers Squibb and Principia/Sanofi and serving as a consultant for Viela Bio and Medpace for work unrelated to this study.

Women with osteoporosis, low bone density, or a previous vertebral fracture show significant increases in the risk of hearing loss compared to those without osteoporosis, according to a new study with more than 3 decades of follow-up.

The use of bisphosphonate therapy did not alter the risk, the researchers found.

“To the best of our knowledge, this is the first large longitudinal study to evaluate the relations of bone density, bisphosphonate use, fractures, and risk of hearing loss,” reported Sharon Curhan, MD, and colleagues in research published online in the Journal of the American Geriatric Society.

“In this large nationwide longitudinal study of nearly 144,000 women with up to 34 years of follow-up, we found that osteoporosis or low bone density was independently associated with higher risk of incident moderate or worse hearing loss,” the authors wrote.

“The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates,” they added.
 

Participants were from the nurses’ health study and NHS II

With recent research suggesting a potential link between bisphosphonate use and prevention of noise-induced hearing loss in mice, Dr. Curhan, of the Channing Division of Network Medicine at Brigham and Women’s Hospital, Boston, and colleagues turned to the large longitudinal cohorts of the Nurses’ Health Study (NHS), conducted from 1982 to 2016, and the Nurses’ Health Study II (NHS II), from 1995 to 2017.

In total, the primary analysis included 60,821 women in the NHS and 83,078 in the NHS II.

Women in the NHS were aged 36-61 years at baseline and 70-95 years at the end of follow-up, while in the NHS II, women were aged 31-48 years at baseline and 53-70 years at the end of follow-up.

After multivariate adjustment for key factors including age, race/ethnicity, oral hormone use, and a variety of other factors, women in the NHS with osteoporosis had an increased risk of moderate or worse hearing loss, as self-reported every 2 years, compared to those without osteoporosis (relative risk, 1.14; 95% confidence interval, 1.09-1.19).

And in the NHS II, which also included data on low bone density, the risk of self-reported hearing loss was higher among those with osteoporosis or low bone density (RR, 1.30; 95% CI, 1.21-1.40).

No significant differences were observed in hearing loss risk based on whether women were treated with bisphosphonates, with the mean duration of use of the medication being 5.8 years in the NHS and 3.4 years in the NHS II.

Those who sustained a vertebral fracture also had a higher risk of hearing loss in both studies (NHS: RR, 1.31; NHS II: RR, 1.39).

However, the increased risk of hearing loss was not observed with hip fracture.

“Our findings of up to a 40% higher risk among women with vertebral fracture, but not hip fracture, were intriguing and merit further study,” the authors noted.

“The discordant findings between these skeletal sites may reflect differences in composition and metabolism of bones in the spine and hip and could provide insight into the pathophysiological changes in the ear that may lead to hearing loss,” they added.
 

Audiometric subanalysis

In an analysis of a subcohort of 3,749 women looking at audiometric thresholds for a more precise measure of hearing loss, women with osteoporosis or low bone density continued to show significantly worse hearing loss when treated with bisphosphonates compared to those without osteoporosis or low bone density.

However, there were no significant hearing loss differences among those with osteoporosis who did not take bisphosphonates versus those without osteoporosis.

The authors speculate that the use of bisphosphonates could have been indicative of more severe osteoporosis, hence the poorer audiometric thresholds.

In an interview, Dr. Curhan said the details of bisphosphonate use, such as type and duration, and their role in hearing loss should be further evaluated.

“Possibly, a potential influence of bisphosphonates on the relation of osteoporosis and hearing loss in humans may depend on the type, dose, and timing of bisphosphonate administration,” she observed. “This is an important question for further study.”
 

Mechanisms: Bone loss may extend to ear structures

In terms of the mechanisms linking osteoporosis itself to hearing loss, the authors noted that bone loss, in addition to compromising more prominent skeletal sites, could logically extend to bone-related structures in the ear.

“Bone mass at peripheral sites is correlated with bone mass at central sites, such as hip and spine, with correlation coefficients between 0.6 and 0.7,” they explained. “Plausibly, systemic bone demineralization could involve the temporal bone, the otic capsule, and the middle ear ossicles.”

They noted that hearing loss has been linked to other pathologic bone disorders, including otosclerosis and Paget disease.

Furthermore, imbalances in bone formation and resorption in osteoporosis may lead to alterations in ionic metabolism, which can lead to hearing loss.

Looking ahead, Dr. Curhan and colleagues plan to further examine whether calcium and vitamin D, which are associated with the prevention of osteoporosis, have a role in preventing hearing loss.

In the meantime, the findings underscore that clinicians treating patients with osteoporosis should routinely check patients’ hearing, Dr. Curhan said.

“Undetected and untreated hearing loss can adversely impact social interactions, physical and mental well-being, and daily life,” she said.

“Early detection of hearing loss offers greater opportunity for successful management and to learn strategies for rehabilitation and prevention of further progression.”

The study received support from the National Institutes of Health.
 

A version of this article first appeared on Medscape.com.

Women with osteoporosis, low bone density, or a previous vertebral fracture show significant increases in the risk of hearing loss compared to those without osteoporosis, according to a new study with more than 3 decades of follow-up.

The use of bisphosphonate therapy did not alter the risk, the researchers found.

“To the best of our knowledge, this is the first large longitudinal study to evaluate the relations of bone density, bisphosphonate use, fractures, and risk of hearing loss,” reported Sharon Curhan, MD, and colleagues in research published online in the Journal of the American Geriatric Society.

“In this large nationwide longitudinal study of nearly 144,000 women with up to 34 years of follow-up, we found that osteoporosis or low bone density was independently associated with higher risk of incident moderate or worse hearing loss,” the authors wrote.

“The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates,” they added.
 

Participants were from the nurses’ health study and NHS II

With recent research suggesting a potential link between bisphosphonate use and prevention of noise-induced hearing loss in mice, Dr. Curhan, of the Channing Division of Network Medicine at Brigham and Women’s Hospital, Boston, and colleagues turned to the large longitudinal cohorts of the Nurses’ Health Study (NHS), conducted from 1982 to 2016, and the Nurses’ Health Study II (NHS II), from 1995 to 2017.

In total, the primary analysis included 60,821 women in the NHS and 83,078 in the NHS II.

Women in the NHS were aged 36-61 years at baseline and 70-95 years at the end of follow-up, while in the NHS II, women were aged 31-48 years at baseline and 53-70 years at the end of follow-up.

After multivariate adjustment for key factors including age, race/ethnicity, oral hormone use, and a variety of other factors, women in the NHS with osteoporosis had an increased risk of moderate or worse hearing loss, as self-reported every 2 years, compared to those without osteoporosis (relative risk, 1.14; 95% confidence interval, 1.09-1.19).

And in the NHS II, which also included data on low bone density, the risk of self-reported hearing loss was higher among those with osteoporosis or low bone density (RR, 1.30; 95% CI, 1.21-1.40).

No significant differences were observed in hearing loss risk based on whether women were treated with bisphosphonates, with the mean duration of use of the medication being 5.8 years in the NHS and 3.4 years in the NHS II.

Those who sustained a vertebral fracture also had a higher risk of hearing loss in both studies (NHS: RR, 1.31; NHS II: RR, 1.39).

However, the increased risk of hearing loss was not observed with hip fracture.

“Our findings of up to a 40% higher risk among women with vertebral fracture, but not hip fracture, were intriguing and merit further study,” the authors noted.

“The discordant findings between these skeletal sites may reflect differences in composition and metabolism of bones in the spine and hip and could provide insight into the pathophysiological changes in the ear that may lead to hearing loss,” they added.
 

Audiometric subanalysis

In an analysis of a subcohort of 3,749 women looking at audiometric thresholds for a more precise measure of hearing loss, women with osteoporosis or low bone density continued to show significantly worse hearing loss when treated with bisphosphonates compared to those without osteoporosis or low bone density.

However, there were no significant hearing loss differences among those with osteoporosis who did not take bisphosphonates versus those without osteoporosis.

The authors speculate that the use of bisphosphonates could have been indicative of more severe osteoporosis, hence the poorer audiometric thresholds.

In an interview, Dr. Curhan said the details of bisphosphonate use, such as type and duration, and their role in hearing loss should be further evaluated.

“Possibly, a potential influence of bisphosphonates on the relation of osteoporosis and hearing loss in humans may depend on the type, dose, and timing of bisphosphonate administration,” she observed. “This is an important question for further study.”
 

Mechanisms: Bone loss may extend to ear structures

In terms of the mechanisms linking osteoporosis itself to hearing loss, the authors noted that bone loss, in addition to compromising more prominent skeletal sites, could logically extend to bone-related structures in the ear.

“Bone mass at peripheral sites is correlated with bone mass at central sites, such as hip and spine, with correlation coefficients between 0.6 and 0.7,” they explained. “Plausibly, systemic bone demineralization could involve the temporal bone, the otic capsule, and the middle ear ossicles.”

They noted that hearing loss has been linked to other pathologic bone disorders, including otosclerosis and Paget disease.

Furthermore, imbalances in bone formation and resorption in osteoporosis may lead to alterations in ionic metabolism, which can lead to hearing loss.

Looking ahead, Dr. Curhan and colleagues plan to further examine whether calcium and vitamin D, which are associated with the prevention of osteoporosis, have a role in preventing hearing loss.

In the meantime, the findings underscore that clinicians treating patients with osteoporosis should routinely check patients’ hearing, Dr. Curhan said.

“Undetected and untreated hearing loss can adversely impact social interactions, physical and mental well-being, and daily life,” she said.

“Early detection of hearing loss offers greater opportunity for successful management and to learn strategies for rehabilitation and prevention of further progression.”

The study received support from the National Institutes of Health.
 

A version of this article first appeared on Medscape.com.

Women with osteoporosis, low bone density, or a previous vertebral fracture show significant increases in the risk of hearing loss compared to those without osteoporosis, according to a new study with more than 3 decades of follow-up.

The use of bisphosphonate therapy did not alter the risk, the researchers found.

“To the best of our knowledge, this is the first large longitudinal study to evaluate the relations of bone density, bisphosphonate use, fractures, and risk of hearing loss,” reported Sharon Curhan, MD, and colleagues in research published online in the Journal of the American Geriatric Society.

“In this large nationwide longitudinal study of nearly 144,000 women with up to 34 years of follow-up, we found that osteoporosis or low bone density was independently associated with higher risk of incident moderate or worse hearing loss,” the authors wrote.

“The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates,” they added.
 

Participants were from the nurses’ health study and NHS II

With recent research suggesting a potential link between bisphosphonate use and prevention of noise-induced hearing loss in mice, Dr. Curhan, of the Channing Division of Network Medicine at Brigham and Women’s Hospital, Boston, and colleagues turned to the large longitudinal cohorts of the Nurses’ Health Study (NHS), conducted from 1982 to 2016, and the Nurses’ Health Study II (NHS II), from 1995 to 2017.

In total, the primary analysis included 60,821 women in the NHS and 83,078 in the NHS II.

Women in the NHS were aged 36-61 years at baseline and 70-95 years at the end of follow-up, while in the NHS II, women were aged 31-48 years at baseline and 53-70 years at the end of follow-up.

After multivariate adjustment for key factors including age, race/ethnicity, oral hormone use, and a variety of other factors, women in the NHS with osteoporosis had an increased risk of moderate or worse hearing loss, as self-reported every 2 years, compared to those without osteoporosis (relative risk, 1.14; 95% confidence interval, 1.09-1.19).

And in the NHS II, which also included data on low bone density, the risk of self-reported hearing loss was higher among those with osteoporosis or low bone density (RR, 1.30; 95% CI, 1.21-1.40).

No significant differences were observed in hearing loss risk based on whether women were treated with bisphosphonates, with the mean duration of use of the medication being 5.8 years in the NHS and 3.4 years in the NHS II.

Those who sustained a vertebral fracture also had a higher risk of hearing loss in both studies (NHS: RR, 1.31; NHS II: RR, 1.39).

However, the increased risk of hearing loss was not observed with hip fracture.

“Our findings of up to a 40% higher risk among women with vertebral fracture, but not hip fracture, were intriguing and merit further study,” the authors noted.

“The discordant findings between these skeletal sites may reflect differences in composition and metabolism of bones in the spine and hip and could provide insight into the pathophysiological changes in the ear that may lead to hearing loss,” they added.
 

Audiometric subanalysis

In an analysis of a subcohort of 3,749 women looking at audiometric thresholds for a more precise measure of hearing loss, women with osteoporosis or low bone density continued to show significantly worse hearing loss when treated with bisphosphonates compared to those without osteoporosis or low bone density.

However, there were no significant hearing loss differences among those with osteoporosis who did not take bisphosphonates versus those without osteoporosis.

The authors speculate that the use of bisphosphonates could have been indicative of more severe osteoporosis, hence the poorer audiometric thresholds.

In an interview, Dr. Curhan said the details of bisphosphonate use, such as type and duration, and their role in hearing loss should be further evaluated.

“Possibly, a potential influence of bisphosphonates on the relation of osteoporosis and hearing loss in humans may depend on the type, dose, and timing of bisphosphonate administration,” she observed. “This is an important question for further study.”
 

Mechanisms: Bone loss may extend to ear structures

In terms of the mechanisms linking osteoporosis itself to hearing loss, the authors noted that bone loss, in addition to compromising more prominent skeletal sites, could logically extend to bone-related structures in the ear.

“Bone mass at peripheral sites is correlated with bone mass at central sites, such as hip and spine, with correlation coefficients between 0.6 and 0.7,” they explained. “Plausibly, systemic bone demineralization could involve the temporal bone, the otic capsule, and the middle ear ossicles.”

They noted that hearing loss has been linked to other pathologic bone disorders, including otosclerosis and Paget disease.

Furthermore, imbalances in bone formation and resorption in osteoporosis may lead to alterations in ionic metabolism, which can lead to hearing loss.

Looking ahead, Dr. Curhan and colleagues plan to further examine whether calcium and vitamin D, which are associated with the prevention of osteoporosis, have a role in preventing hearing loss.

In the meantime, the findings underscore that clinicians treating patients with osteoporosis should routinely check patients’ hearing, Dr. Curhan said.

“Undetected and untreated hearing loss can adversely impact social interactions, physical and mental well-being, and daily life,” she said.

“Early detection of hearing loss offers greater opportunity for successful management and to learn strategies for rehabilitation and prevention of further progression.”

The study received support from the National Institutes of Health.
 

A version of this article first appeared on Medscape.com.

OnabotulinumtoxinA alone provides relief from chronic migraine, and addition of anti-calcitonin gene-related peptide (CGRP) antibodies may boost the benefit, according to a large retrospective analysis. The results lend hope that the combination may be synergistic, according to Andrew Blumenfeld, MD, director of the Headache Center of Southern California in Carlsbad. Dr. Blumenfeld presented at the American Headache Society’s 2021 annual meeting. The study was published online April 21 in Pain Therapy.

The retrospective analysis showed a 4-day reduction in headache days per month. In contrast, in the pivotal study for erenumab, the most commonly used anti-CGRP antibody among subjects in the study, showed a 2-day benefit in a subanalysis of patients who had failed at least two oral preventives.

There is mechanistic evidence to suggest the two therapies could be synergistic. OnabotulinumtoxinA is believed to inhibit the release of CGRP, and antibodies reduce CGRP levels. OnabotulinumtoxinA prevents activation of C-fibers in the trigeminal sensory afferents, but does not affect A-delta fibers.

On the other hand, most data indicate that the anti-CGRP antibody fremanezumab prevents activation of A-delta but not C-fibers, and a recent review argues that CGRP antibody nonresponders may have migraines driven by C-fibers or other pathways. “Thus, concomitant use of medications blocking the activation of meningeal C-fibers may provide a synergistic effect on the trigeminal nociceptive pathway,” the authors wrote.
 

Study finding match clinical practice

The results of the new study strengthen the case that the combination is effective, though proof would require prospective, randomized trials. “I think that it really gives credibility to what we are seeing in practice, which is that combined therapy often is much better than therapy with onabotulinumtoxinA alone, said Deborah Friedman, MD, MPH, who was asked to comment on the findings. Dr. Friedman is professor of neurology and ophthalmology at the University of Texas, Dallas.

The extra 4 migraine-free days per month is a significant benefit, said Stewart Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H. “It’s an extra month and a half of no disability per year, and that’s on top of what onabotulinumtoxinA does. So it’s really a very important clinical finding,” Dr. Tepper said in an interview.

Improvements with combination therapy

The study was a chart review of 257 patients who started on onabotulinumtoxinA and later initiated anti-CGRP antibody therapy. A total of 104 completed four visits after initiation of anti-CGRP antibody therapy (completers). Before starting any therapy, patients reported an average of 21 headache days per month in the overall group, and 22 among completers. That frequency dropped to 12 in both groups after onabotulinumtoxinA therapy (overall group difference, –9 days; 95% confidence interval, –8 to –11 days; completers group difference, –10; 95% CI, –7 to –12 days).

A total of 77.8% of subjects in the overall cohort took erenumab, 16.3% took galcanezumab, and 5.8% took fremanezumab. In the completers cohort, the percentages were 84.5%, 10.7%, and 4.9%, respectively.

Compared with baseline, both completers and noncompleters had clinically significant improvements in disability, as measured by at least a 5-point improvement in Migraine Disability Assessment (MIDAS) score at the 3-month visit (–5.8 for completers and –6.3 for the overall cohort group), the 6-month visit (–6.6 and –11.1), the 9-month visit (–8.3 and –6.1), and 1 year (–12.7 and –8.4).

At the first visit, 33.0% of completers had at least a 5-point reduction in MIDAS, as did 36.0% of the overall cohort group, and the trend continued at 6 months (39.8% and 45.1%), 9 months (43.7% and 43.7%), and at 1 year (45.3% and 44.8%).

The study was funded by Allergan. Dr. Blumenfeld has served on advisory boards for Aeon, AbbVie, Amgen, Alder, Biohaven, Teva, Supernus, Promius, Eaglet, and Lilly, and has received funding for speaking from AbbVie, Amgen, Pernix, Supernus, Depomed, Avanir, Promius, Teva, Eli Lilly, Lundbeck, Novartis, and Theranica. Dr. Tepper has consulted for Teva. Dr. Friedman has been on the advisory board for Allergan, Amgen, Lundbeck, Eli Lilly, and Teva Pharmaceuticals, and has received grant support from Allergan and Eli Lilly.

OnabotulinumtoxinA alone provides relief from chronic migraine, and addition of anti-calcitonin gene-related peptide (CGRP) antibodies may boost the benefit, according to a large retrospective analysis. The results lend hope that the combination may be synergistic, according to Andrew Blumenfeld, MD, director of the Headache Center of Southern California in Carlsbad. Dr. Blumenfeld presented at the American Headache Society’s 2021 annual meeting. The study was published online April 21 in Pain Therapy.

The retrospective analysis showed a 4-day reduction in headache days per month. In contrast, in the pivotal study for erenumab, the most commonly used anti-CGRP antibody among subjects in the study, showed a 2-day benefit in a subanalysis of patients who had failed at least two oral preventives.

There is mechanistic evidence to suggest the two therapies could be synergistic. OnabotulinumtoxinA is believed to inhibit the release of CGRP, and antibodies reduce CGRP levels. OnabotulinumtoxinA prevents activation of C-fibers in the trigeminal sensory afferents, but does not affect A-delta fibers.

On the other hand, most data indicate that the anti-CGRP antibody fremanezumab prevents activation of A-delta but not C-fibers, and a recent review argues that CGRP antibody nonresponders may have migraines driven by C-fibers or other pathways. “Thus, concomitant use of medications blocking the activation of meningeal C-fibers may provide a synergistic effect on the trigeminal nociceptive pathway,” the authors wrote.
 

Study finding match clinical practice

The results of the new study strengthen the case that the combination is effective, though proof would require prospective, randomized trials. “I think that it really gives credibility to what we are seeing in practice, which is that combined therapy often is much better than therapy with onabotulinumtoxinA alone, said Deborah Friedman, MD, MPH, who was asked to comment on the findings. Dr. Friedman is professor of neurology and ophthalmology at the University of Texas, Dallas.

The extra 4 migraine-free days per month is a significant benefit, said Stewart Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H. “It’s an extra month and a half of no disability per year, and that’s on top of what onabotulinumtoxinA does. So it’s really a very important clinical finding,” Dr. Tepper said in an interview.

Improvements with combination therapy

The study was a chart review of 257 patients who started on onabotulinumtoxinA and later initiated anti-CGRP antibody therapy. A total of 104 completed four visits after initiation of anti-CGRP antibody therapy (completers). Before starting any therapy, patients reported an average of 21 headache days per month in the overall group, and 22 among completers. That frequency dropped to 12 in both groups after onabotulinumtoxinA therapy (overall group difference, –9 days; 95% confidence interval, –8 to –11 days; completers group difference, –10; 95% CI, –7 to –12 days).

A total of 77.8% of subjects in the overall cohort took erenumab, 16.3% took galcanezumab, and 5.8% took fremanezumab. In the completers cohort, the percentages were 84.5%, 10.7%, and 4.9%, respectively.

Compared with baseline, both completers and noncompleters had clinically significant improvements in disability, as measured by at least a 5-point improvement in Migraine Disability Assessment (MIDAS) score at the 3-month visit (–5.8 for completers and –6.3 for the overall cohort group), the 6-month visit (–6.6 and –11.1), the 9-month visit (–8.3 and –6.1), and 1 year (–12.7 and –8.4).

At the first visit, 33.0% of completers had at least a 5-point reduction in MIDAS, as did 36.0% of the overall cohort group, and the trend continued at 6 months (39.8% and 45.1%), 9 months (43.7% and 43.7%), and at 1 year (45.3% and 44.8%).

The study was funded by Allergan. Dr. Blumenfeld has served on advisory boards for Aeon, AbbVie, Amgen, Alder, Biohaven, Teva, Supernus, Promius, Eaglet, and Lilly, and has received funding for speaking from AbbVie, Amgen, Pernix, Supernus, Depomed, Avanir, Promius, Teva, Eli Lilly, Lundbeck, Novartis, and Theranica. Dr. Tepper has consulted for Teva. Dr. Friedman has been on the advisory board for Allergan, Amgen, Lundbeck, Eli Lilly, and Teva Pharmaceuticals, and has received grant support from Allergan and Eli Lilly.

OnabotulinumtoxinA alone provides relief from chronic migraine, and addition of anti-calcitonin gene-related peptide (CGRP) antibodies may boost the benefit, according to a large retrospective analysis. The results lend hope that the combination may be synergistic, according to Andrew Blumenfeld, MD, director of the Headache Center of Southern California in Carlsbad. Dr. Blumenfeld presented at the American Headache Society’s 2021 annual meeting. The study was published online April 21 in Pain Therapy.

The retrospective analysis showed a 4-day reduction in headache days per month. In contrast, in the pivotal study for erenumab, the most commonly used anti-CGRP antibody among subjects in the study, showed a 2-day benefit in a subanalysis of patients who had failed at least two oral preventives.

There is mechanistic evidence to suggest the two therapies could be synergistic. OnabotulinumtoxinA is believed to inhibit the release of CGRP, and antibodies reduce CGRP levels. OnabotulinumtoxinA prevents activation of C-fibers in the trigeminal sensory afferents, but does not affect A-delta fibers.

On the other hand, most data indicate that the anti-CGRP antibody fremanezumab prevents activation of A-delta but not C-fibers, and a recent review argues that CGRP antibody nonresponders may have migraines driven by C-fibers or other pathways. “Thus, concomitant use of medications blocking the activation of meningeal C-fibers may provide a synergistic effect on the trigeminal nociceptive pathway,” the authors wrote.
 

Study finding match clinical practice

The results of the new study strengthen the case that the combination is effective, though proof would require prospective, randomized trials. “I think that it really gives credibility to what we are seeing in practice, which is that combined therapy often is much better than therapy with onabotulinumtoxinA alone, said Deborah Friedman, MD, MPH, who was asked to comment on the findings. Dr. Friedman is professor of neurology and ophthalmology at the University of Texas, Dallas.

The extra 4 migraine-free days per month is a significant benefit, said Stewart Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H. “It’s an extra month and a half of no disability per year, and that’s on top of what onabotulinumtoxinA does. So it’s really a very important clinical finding,” Dr. Tepper said in an interview.

Improvements with combination therapy

The study was a chart review of 257 patients who started on onabotulinumtoxinA and later initiated anti-CGRP antibody therapy. A total of 104 completed four visits after initiation of anti-CGRP antibody therapy (completers). Before starting any therapy, patients reported an average of 21 headache days per month in the overall group, and 22 among completers. That frequency dropped to 12 in both groups after onabotulinumtoxinA therapy (overall group difference, –9 days; 95% confidence interval, –8 to –11 days; completers group difference, –10; 95% CI, –7 to –12 days).

A total of 77.8% of subjects in the overall cohort took erenumab, 16.3% took galcanezumab, and 5.8% took fremanezumab. In the completers cohort, the percentages were 84.5%, 10.7%, and 4.9%, respectively.

Compared with baseline, both completers and noncompleters had clinically significant improvements in disability, as measured by at least a 5-point improvement in Migraine Disability Assessment (MIDAS) score at the 3-month visit (–5.8 for completers and –6.3 for the overall cohort group), the 6-month visit (–6.6 and –11.1), the 9-month visit (–8.3 and –6.1), and 1 year (–12.7 and –8.4).

At the first visit, 33.0% of completers had at least a 5-point reduction in MIDAS, as did 36.0% of the overall cohort group, and the trend continued at 6 months (39.8% and 45.1%), 9 months (43.7% and 43.7%), and at 1 year (45.3% and 44.8%).

The study was funded by Allergan. Dr. Blumenfeld has served on advisory boards for Aeon, AbbVie, Amgen, Alder, Biohaven, Teva, Supernus, Promius, Eaglet, and Lilly, and has received funding for speaking from AbbVie, Amgen, Pernix, Supernus, Depomed, Avanir, Promius, Teva, Eli Lilly, Lundbeck, Novartis, and Theranica. Dr. Tepper has consulted for Teva. Dr. Friedman has been on the advisory board for Allergan, Amgen, Lundbeck, Eli Lilly, and Teva Pharmaceuticals, and has received grant support from Allergan and Eli Lilly.

Converge 2021 session

Racial and Gender Equity in Your PHM Program

Presenters

Jorge Ganem, MD, FAAP, and Vanessa N. Durand, DO, FAAP

Session summary

Dr. Ganem, associate professor of pediatrics at the University of Texas at Austin and director of pediatric hospital medicine at Dell Children’s Medical Center, and Dr. Durand, assistant professor of pediatrics at Drexel University and pediatric hospitalist at St. Christopher’s Hospital for Children, Philadelphia, presented an engaging session regarding gender equity in the workplace during SHM Converge 2021.

Dr. Ganem and Dr. Durand first presented data to illustrate the gender equity problem. They touched on the mental burden underrepresented minorities face professionally. Dr. Ganem and Dr. Durand discussed cognitive biases, defined allyship, sponsorship, and mentorship and shared how to distinguish between the three. They concluded their session with concrete ways to narrow gaps in equity in hospital medicine programs.

The highlights of this session included evidence-based “best-practices” that pediatric hospital medicine divisions can adopt. One important theme was regarding metrics. Dr. Ganem and Dr. Durand shared how important it is to evaluate divisions for pay and diversity gaps. Armed with these data, programs can be more effective in developing solutions. Some solutions provided by the presenters included “blind” interviews where traditional “cognitive metrics” (i.e., board scores) are not shared with interviewers to minimize anchoring and confirmation biases. Instead, interviewers should focus on the experiences and attributes of the job that the applicant can hopefully embody. This could be accomplished using a holistic review tool from the Association of American Medical Colleges.

One of the most powerful ideas shared in this session was a quote from a Harvard student shown in a video regarding bias and racism where he said, “Nothing in all the world is more dangerous than sincere ignorance and conscious stupidity.” Changes will only happen if we make them happen.

Key takeaways

• Racial and gender equity are problems that are undeniable, even in pediatrics.
• Be wary of conscious biases and the mental burden placed unfairly on underrepresented minorities in your institution.
• Becoming an amplifier, a sponsor, or a champion are ways to make a small individual difference.
• Measure your program’s data and commit to making change using evidence-based actions and assessments aimed at decreasing bias and increasing equity.

References

Association of American Medical Colleges. Holistic Review. 2021. www.aamc.org/services/member-capacity-building/holistic-review.

Dr. Singh is a board-certified pediatric hospitalist at Stanford University and Lucile Packard Children’s Hospital Stanford, both in Palo Alto, Calif. He is a native Texan living in the San Francisco Bay area with his wife and two young boys. His nonclinical passions include bedside communication and inpatient health care information technology.

Converge 2021 session

Racial and Gender Equity in Your PHM Program

Presenters

Jorge Ganem, MD, FAAP, and Vanessa N. Durand, DO, FAAP

Session summary

Dr. Ganem, associate professor of pediatrics at the University of Texas at Austin and director of pediatric hospital medicine at Dell Children’s Medical Center, and Dr. Durand, assistant professor of pediatrics at Drexel University and pediatric hospitalist at St. Christopher’s Hospital for Children, Philadelphia, presented an engaging session regarding gender equity in the workplace during SHM Converge 2021.

Dr. Ganem and Dr. Durand first presented data to illustrate the gender equity problem. They touched on the mental burden underrepresented minorities face professionally. Dr. Ganem and Dr. Durand discussed cognitive biases, defined allyship, sponsorship, and mentorship and shared how to distinguish between the three. They concluded their session with concrete ways to narrow gaps in equity in hospital medicine programs.

The highlights of this session included evidence-based “best-practices” that pediatric hospital medicine divisions can adopt. One important theme was regarding metrics. Dr. Ganem and Dr. Durand shared how important it is to evaluate divisions for pay and diversity gaps. Armed with these data, programs can be more effective in developing solutions. Some solutions provided by the presenters included “blind” interviews where traditional “cognitive metrics” (i.e., board scores) are not shared with interviewers to minimize anchoring and confirmation biases. Instead, interviewers should focus on the experiences and attributes of the job that the applicant can hopefully embody. This could be accomplished using a holistic review tool from the Association of American Medical Colleges.

One of the most powerful ideas shared in this session was a quote from a Harvard student shown in a video regarding bias and racism where he said, “Nothing in all the world is more dangerous than sincere ignorance and conscious stupidity.” Changes will only happen if we make them happen.

Key takeaways

• Racial and gender equity are problems that are undeniable, even in pediatrics.
• Be wary of conscious biases and the mental burden placed unfairly on underrepresented minorities in your institution.
• Becoming an amplifier, a sponsor, or a champion are ways to make a small individual difference.
• Measure your program’s data and commit to making change using evidence-based actions and assessments aimed at decreasing bias and increasing equity.

References

Association of American Medical Colleges. Holistic Review. 2021. www.aamc.org/services/member-capacity-building/holistic-review.

Dr. Singh is a board-certified pediatric hospitalist at Stanford University and Lucile Packard Children’s Hospital Stanford, both in Palo Alto, Calif. He is a native Texan living in the San Francisco Bay area with his wife and two young boys. His nonclinical passions include bedside communication and inpatient health care information technology.

Converge 2021 session

Racial and Gender Equity in Your PHM Program

Presenters

Jorge Ganem, MD, FAAP, and Vanessa N. Durand, DO, FAAP

Session summary

Dr. Ganem, associate professor of pediatrics at the University of Texas at Austin and director of pediatric hospital medicine at Dell Children’s Medical Center, and Dr. Durand, assistant professor of pediatrics at Drexel University and pediatric hospitalist at St. Christopher’s Hospital for Children, Philadelphia, presented an engaging session regarding gender equity in the workplace during SHM Converge 2021.

Dr. Ganem and Dr. Durand first presented data to illustrate the gender equity problem. They touched on the mental burden underrepresented minorities face professionally. Dr. Ganem and Dr. Durand discussed cognitive biases, defined allyship, sponsorship, and mentorship and shared how to distinguish between the three. They concluded their session with concrete ways to narrow gaps in equity in hospital medicine programs.

The highlights of this session included evidence-based “best-practices” that pediatric hospital medicine divisions can adopt. One important theme was regarding metrics. Dr. Ganem and Dr. Durand shared how important it is to evaluate divisions for pay and diversity gaps. Armed with these data, programs can be more effective in developing solutions. Some solutions provided by the presenters included “blind” interviews where traditional “cognitive metrics” (i.e., board scores) are not shared with interviewers to minimize anchoring and confirmation biases. Instead, interviewers should focus on the experiences and attributes of the job that the applicant can hopefully embody. This could be accomplished using a holistic review tool from the Association of American Medical Colleges.

One of the most powerful ideas shared in this session was a quote from a Harvard student shown in a video regarding bias and racism where he said, “Nothing in all the world is more dangerous than sincere ignorance and conscious stupidity.” Changes will only happen if we make them happen.

Key takeaways

• Racial and gender equity are problems that are undeniable, even in pediatrics.
• Be wary of conscious biases and the mental burden placed unfairly on underrepresented minorities in your institution.
• Becoming an amplifier, a sponsor, or a champion are ways to make a small individual difference.
• Measure your program’s data and commit to making change using evidence-based actions and assessments aimed at decreasing bias and increasing equity.

References

Association of American Medical Colleges. Holistic Review. 2021. www.aamc.org/services/member-capacity-building/holistic-review.

Dr. Singh is a board-certified pediatric hospitalist at Stanford University and Lucile Packard Children’s Hospital Stanford, both in Palo Alto, Calif. He is a native Texan living in the San Francisco Bay area with his wife and two young boys. His nonclinical passions include bedside communication and inpatient health care information technology.