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Impact of VA Hematology/Oncology Clinical Pharmacy Practitioners in the Review of Community Prescriptions for Specialty Medications
The value of a hematology/oncology clinical pharmacy practitioner (CPP) has been validated in several studies documenting their positive impact on patient outcomes, supportive care management, laboratory monitoring, medication error identification, and drug expenditure.1-6 With> 200 oncology-related US Food and Drug Administration approval notifications published from 2020 to 2023, it is no surprise that national trends in oncology drug clinic expenditures increased from $39.9 billion in 2020 to $44.1 billion in 2021.7,8 With the rapidly changing treatment landscape, new drug approvals, and risk of polypharmacy, oral anticancer agents carry a high risk for medication errors.4 Additional challenges include complex dosing regimens and instructions, adherence issues, drug interactions, adjustments for organ dysfunction, and extensive adverse effect (AE) profiles.
Because of the niche and complexity of oral anticancer agents, trained CPPs havehematology/oncology education and expertise that pharmacists without specialized training lack. A survey of 243 nonspecialized community pharmacists that assessed their knowledge of oral anticancer therapies revealed that only about half of the knowledge questions were answered correctly, illustrating an education gap among these pharmacists.9 The Hematology/Oncology Pharmacist Association's suggests that best practices for managing oral oncology therapy should include comprehensive medication review by an oncology-trained pharmacist for each prescription.10
The US Department of Veterans Affairs (VA) community care network, which was established by the MISSION Act, allows covered access for eligible veterans in the local community outside of the VA network. Unfortunately, this dual-system use of health care could increase the risk of poorly coordinated care and has been associated with the risk of inappropriate prescribing.11,12 It is unclear how many private practices enrolled in the community care program have access to oncology-trained pharmacists. Specialized pharmaceutical reviews of oral anticancer medication prescriptions from these practices are vital for veteran care. This study evaluates the clinical and financial interventions of hematology/oncology CPPs review of specialty hematology/oncology prescriptions from community care health care practitioners (HCPs) at the Veterans Affairs North Texas Health Care System (VANTHCS) in Dallas.
METHODS
This study is a retrospective review of Computerized Patient Record System (CPRS) records of patients at VANTHCS from January 1, 2015, to June 30, 2023. Patients included were aged ≥ 18 years, enrolled in the VA community care program, received a specialty hematology/oncology medication that was dispensed through VA pharmacies or VA-contracted pharmacies, and had an hematology/oncology CPP medication review documented in CPRS. The primary aim of this study was to assess the number and types of clinical interventions performed. A clinical intervention was defined as a documented communication attempt with a community care HCP or direct communication with a patient to address a specific medication-related issue noted during CPP review.
Review of specialty hematology/oncology medications by a hematology/oncology CPP included evaluation of therapy indication, such as whether the prescription meets clinical guidelines, VA criteria for use, or other clinical literature as judged appropriate by the CPP. In some cases, the CPP requested that the community care HCP prescribe a more cost-effective or formulary-preferred agent. Each prescription was reviewed for dosage and formulation appropriateness, drug interactions with available medication lists, baseline laboratory test completion, and recommended supportive care medicines. At times, patient counseling is completed as part of the clinical review. When necessary, CPPs could discuss patient cases with a VA-employed oncologist for further oversight regarding appropriateness and safety. Secondary outcomes included the number of interventions accepted or denied by the prescriber provider and cost savings.
Data collected included the type of malignancy, hematology/oncology specialty medication requested, number and type of interventions sent to the community care prescriber, number of interventions accepted or denied by the community care prescriber, and whether the CPP conducted patient counseling or dispensed or denied the product. Cost savings were calculated for medications that were denied or changed to a formulary preferred or cost-effective agent using pricing data from the National Acquisition Center Contract Catalog or Federal Supply Schedule Service as of April 2024.
RESULTS
A total of 221 hematology/oncology prescriptions met inclusion criteria. Among patients receiving these prescriptions, the median age was 70 years and 91% were male. The most common malignancies included 31 instances of multiple myeloma (14%), 26 for chronic lymphocytic leukemia (12%), 24 for prostate cancer (11%), 23 for glioblastoma/brain cancer (10%), 18 for renal cell carcinoma (8%), 17 for colorectal cancer (8%), and 15 for acute myeloid leukemia (7%). Clinical interventions by the hematology/oncology CPP were completed for 82 (37%) of the 221 prescriptions. One clinical intervention was communicated directly to the patient, and attempts were made to communicate with the community care HCP for the remaining 81 prescriptions. The CPP documented 97 clinical interventions for the 82 prescriptions (Table 1). The most commonly documented clinical interventions included: 25 for managing/preventing a drug interaction (26%), 24 for dose adjustment request (25%), 13 for prescription denial (13%), and 11 for requesting the use of a preferred or more cost-effective product (11%). Of note, 16 patients (7%) received counseling from the hematology/oncology CPP. Ten patients (5%) received counseling alone with no other intervention and did not meet the definition of a clinical intervention.
The most frequent prescriptions requiring intervention included 8 for enzalutamide, 7 for venetoclax, 6 for ibrutinib, and 5 each for lenalidomide, cabozantinib, and temozolomide. Among the 97 interventions, 68 were approved (70%), 15 received no response (16%), and 14 were denied by the community care HCP (14%). Despite obtaining no response or intervention denial from the community care HCP, hematology/oncology CPPs could approve these prescriptions if clinically appropriate, and their reasoning was documented. Table 2 further describes the types of interventions that were denied or obtained no response by the community care practitioner. Among the prescriptions denied by the hematology/oncology CPP, 11 were rejected for off-label indications and/or did not have support through primary literature, national guidelines, or VA criteria for use. Only 2 prescriptions were denied for safety concerns.
These documented clinical interventions had financial implications. For drugs with available cost data, requesting the use of a preferred/cost-effective product led to estimated savings of at least $263,536 over the study period with some ongoing cost savings. Prescription denials led to further estimated savings of $186,275 per month, although this is limited by the lack of known costs of alternative therapies the community care physicians chose.
DISCUSSION
More than one-third of prescriptions required clinical interventions, and 70% of these interventions were accepted by the community care prescriber, demonstrating the CPP’s essential role. Results indicate that most CPP clinical interventions involved clarifying and correcting doses, managing pertinent drug interactions, and ensuring appropriate use of medications according to clinical and national VA guidelines. Other studies have examined the impact of CPPs on patient care and cancer treatment.5,6 The randomized, multicenter AMBORA trial found that clinical pharmacist support reduced severe AEs and medication errors related to oral anticancer agents.5 The per-patient mean number of medication errors found by pharmacist review was 1.7 (range, 0 to 9), with most medication errors noted at the prescribing stage.5 Suzuki and colleagues analyzed data from 35,062 chemotherapy regimens and found that 53.1% of the chemotherapy prescriptions were modified because of pharmacist interventions.6 The most common reason for prescription modifications was prescription error.
Most of the clinical interventions in this study were accepted by community HCPs, indicating that these prescribers are receptive to hematology/oncology CPP input. Among those with no response, most were in relation to recommendations regarding drug interactions. In most of these cases, the drug interaction was not clinically concerning enough to require a response before the CPP approved the prescription. Therefore, it is unknown whether the outside HCP implemented the clinical recommendations. The most common types of clinical interventions the community care HCP declined were dose adjustment requests or requests to switch to a more cost-effective/formulary-preferred agent. In these cases, the prescriber’s preference was documented and, if clinically appropriate, approved by the CPP.
Although the financial implications of CPP clinical interventions were only marginally evaluated in this review, results suggest that cost savings by requests to switch to a cost-effective/formulary preferred agent or prescription denials are substantial. Because of changes in prescription costs over time, it is possible that savings from CPP intervention were greater than calculations using current Federal Supply Schedule Service pricing. The total impact of CPP prescription interventions on reducing or preventing hospitalizations or AEs is not known from this review, but other data suggest that cost savings may benefit the system.13,14
Limitations
This study's retrospective design is a limitation because practice patterns at the VANTHCS involving multiple hematology/oncology CPPs review of community care prescriptions might have evolved over time. The total financial implications of CPP interventions cannot fully be elucidated. The cost of alternative therapies used for patients who received a prescription denial is not factored into this review.
Conclusions
VANTHCS CPPs played an essential role in reviewing anticancer medication prescriptions from community care prescribers. In this study, CPP clinical interventions were completed for more than one-third of the prescriptions and the community-based HCP approved most of these interventions. These changes also resulted in financial benefits.
These findings add to the body of literature emphasizing the need for hematology/oncology-trained CPPs to review anticancer prescriptions and treatment plans. Our review could be used to justify CPP involvement in community care specialty medication review at VA facilities that do not currently have CPP involvement.
1. Shah NN, Casella E, Capozzi D, et al. Improving the safety of oral chemotherapy at an academic medical center. J Oncol Pract. 2016;12(1):e71-e76. doi:10.1200/JOP.2015.007260
2. Gatwood J, Gatwood K, Gabre E, Alexander M. Impact of clinical pharmacists in outpatient oncology practices: a review. Am J Health Syst Pharm. 2017;74(19):1549-1557. doi:10.2146/ajhp160475
3. Lankford C, Dura J, Tran A, et al. Effect of clinical pharmacist interventions on cost in an integrated health system specialty pharmacy. J Manag Care Spec Pharm. 2021;27(3):379-384. doi:10.18553/jmcp.2021.27.3.379
4. Schlichtig K, Dürr P, Dörje F, Fromm MF. Medication errors during treatment with new oral anticancer agents: consequences for clinical practice based on the AMBORA Study. Clin Pharmacol Ther. 2021;110(4):1075-1086. doi:10.1002/cpt.2338
5. Dürr P, Schlichtig K, Kelz C, et al. The randomized AMBORA Trial: impact of pharmacological/pharmaceutical care on medication safety and patient-reported outcomes during treatment with new oral anticancer agents. J Clin Oncol. 2021;39(18):1983-1994. doi:10.1200/JCO.20.03088
6. Suzuki S, Chan A, Nomura H, Johnson PE, Endo K, Saito S. Chemotherapy regimen checks performed by pharmacists contribute to safe administration of chemotherapy. J Oncol Pharm Pract. 2017;23(1):18-25. doi:10.1177/1078155215614998
7. Tichy EM, Hoffman JM, Suda KJ, et al. National trends in prescription drug expenditures and projections for 2022. Am J Health Syst Pharm. 2022;79(14):1158-1172. doi:10.1093/ajhp/zxac102
8. US Food and Drug Administration. Oncology (cancer)/hematologic malignancies approval notifications. 2023.
9. O’Bryant CL, Crandell BC. Community pharmacists’ knowledge of and attitudes toward oral chemotherapy. J Am Pharm Assoc (2003). 2008;48(5):632-639. doi:10.1331/JAPhA.2008.07082
10. Mackler E, Segal EM, Muluneh B, Jeffers K, Carmichael J. 2018 hematology/oncology pharmacist association best practices for the management of oral oncolytic therapy: pharmacy practice standard. J Oncol Pract. 2019;15(4):e346-e355. doi:10.1200/JOP.18.00581
11. Thorpe JM, Thorpe CT, Schleiden L, et al. Association between dual use of Department of Veterans Affairs and Medicare part D drug benefits and potentially unsafe prescribing. JAMA Intern Med. 2019;179(11):1584-1586. doi:10.1001/jamainternmed.2019.2788
12. Thorpe JM, Thorpe CT, Gellad WF, et al. Dual health care system use and high-risk prescribing in patients with dementia: a national cohort study. Ann Intern Med. 2017;166(3):157-163. doi:10.7326/M16-0551
13. Chen P-Z, Wu C-C, Huang C-F. Clinical and economic impact of clinical pharmacist intervention in a hematology unit. J Oncol Pharm Pract. 2020;26(4):866-872. doi:10.1177/1078155219875806
14. Dalton K, Byrne S. Role of the pharmacist in reducing healthcare costs: current insights. Integr Pharm Res Pract. 2017;6:37-46. doi:10.2147/IPRP.S108047
The value of a hematology/oncology clinical pharmacy practitioner (CPP) has been validated in several studies documenting their positive impact on patient outcomes, supportive care management, laboratory monitoring, medication error identification, and drug expenditure.1-6 With> 200 oncology-related US Food and Drug Administration approval notifications published from 2020 to 2023, it is no surprise that national trends in oncology drug clinic expenditures increased from $39.9 billion in 2020 to $44.1 billion in 2021.7,8 With the rapidly changing treatment landscape, new drug approvals, and risk of polypharmacy, oral anticancer agents carry a high risk for medication errors.4 Additional challenges include complex dosing regimens and instructions, adherence issues, drug interactions, adjustments for organ dysfunction, and extensive adverse effect (AE) profiles.
Because of the niche and complexity of oral anticancer agents, trained CPPs havehematology/oncology education and expertise that pharmacists without specialized training lack. A survey of 243 nonspecialized community pharmacists that assessed their knowledge of oral anticancer therapies revealed that only about half of the knowledge questions were answered correctly, illustrating an education gap among these pharmacists.9 The Hematology/Oncology Pharmacist Association's suggests that best practices for managing oral oncology therapy should include comprehensive medication review by an oncology-trained pharmacist for each prescription.10
The US Department of Veterans Affairs (VA) community care network, which was established by the MISSION Act, allows covered access for eligible veterans in the local community outside of the VA network. Unfortunately, this dual-system use of health care could increase the risk of poorly coordinated care and has been associated with the risk of inappropriate prescribing.11,12 It is unclear how many private practices enrolled in the community care program have access to oncology-trained pharmacists. Specialized pharmaceutical reviews of oral anticancer medication prescriptions from these practices are vital for veteran care. This study evaluates the clinical and financial interventions of hematology/oncology CPPs review of specialty hematology/oncology prescriptions from community care health care practitioners (HCPs) at the Veterans Affairs North Texas Health Care System (VANTHCS) in Dallas.
METHODS
This study is a retrospective review of Computerized Patient Record System (CPRS) records of patients at VANTHCS from January 1, 2015, to June 30, 2023. Patients included were aged ≥ 18 years, enrolled in the VA community care program, received a specialty hematology/oncology medication that was dispensed through VA pharmacies or VA-contracted pharmacies, and had an hematology/oncology CPP medication review documented in CPRS. The primary aim of this study was to assess the number and types of clinical interventions performed. A clinical intervention was defined as a documented communication attempt with a community care HCP or direct communication with a patient to address a specific medication-related issue noted during CPP review.
Review of specialty hematology/oncology medications by a hematology/oncology CPP included evaluation of therapy indication, such as whether the prescription meets clinical guidelines, VA criteria for use, or other clinical literature as judged appropriate by the CPP. In some cases, the CPP requested that the community care HCP prescribe a more cost-effective or formulary-preferred agent. Each prescription was reviewed for dosage and formulation appropriateness, drug interactions with available medication lists, baseline laboratory test completion, and recommended supportive care medicines. At times, patient counseling is completed as part of the clinical review. When necessary, CPPs could discuss patient cases with a VA-employed oncologist for further oversight regarding appropriateness and safety. Secondary outcomes included the number of interventions accepted or denied by the prescriber provider and cost savings.
Data collected included the type of malignancy, hematology/oncology specialty medication requested, number and type of interventions sent to the community care prescriber, number of interventions accepted or denied by the community care prescriber, and whether the CPP conducted patient counseling or dispensed or denied the product. Cost savings were calculated for medications that were denied or changed to a formulary preferred or cost-effective agent using pricing data from the National Acquisition Center Contract Catalog or Federal Supply Schedule Service as of April 2024.
RESULTS
A total of 221 hematology/oncology prescriptions met inclusion criteria. Among patients receiving these prescriptions, the median age was 70 years and 91% were male. The most common malignancies included 31 instances of multiple myeloma (14%), 26 for chronic lymphocytic leukemia (12%), 24 for prostate cancer (11%), 23 for glioblastoma/brain cancer (10%), 18 for renal cell carcinoma (8%), 17 for colorectal cancer (8%), and 15 for acute myeloid leukemia (7%). Clinical interventions by the hematology/oncology CPP were completed for 82 (37%) of the 221 prescriptions. One clinical intervention was communicated directly to the patient, and attempts were made to communicate with the community care HCP for the remaining 81 prescriptions. The CPP documented 97 clinical interventions for the 82 prescriptions (Table 1). The most commonly documented clinical interventions included: 25 for managing/preventing a drug interaction (26%), 24 for dose adjustment request (25%), 13 for prescription denial (13%), and 11 for requesting the use of a preferred or more cost-effective product (11%). Of note, 16 patients (7%) received counseling from the hematology/oncology CPP. Ten patients (5%) received counseling alone with no other intervention and did not meet the definition of a clinical intervention.
The most frequent prescriptions requiring intervention included 8 for enzalutamide, 7 for venetoclax, 6 for ibrutinib, and 5 each for lenalidomide, cabozantinib, and temozolomide. Among the 97 interventions, 68 were approved (70%), 15 received no response (16%), and 14 were denied by the community care HCP (14%). Despite obtaining no response or intervention denial from the community care HCP, hematology/oncology CPPs could approve these prescriptions if clinically appropriate, and their reasoning was documented. Table 2 further describes the types of interventions that were denied or obtained no response by the community care practitioner. Among the prescriptions denied by the hematology/oncology CPP, 11 were rejected for off-label indications and/or did not have support through primary literature, national guidelines, or VA criteria for use. Only 2 prescriptions were denied for safety concerns.
These documented clinical interventions had financial implications. For drugs with available cost data, requesting the use of a preferred/cost-effective product led to estimated savings of at least $263,536 over the study period with some ongoing cost savings. Prescription denials led to further estimated savings of $186,275 per month, although this is limited by the lack of known costs of alternative therapies the community care physicians chose.
DISCUSSION
More than one-third of prescriptions required clinical interventions, and 70% of these interventions were accepted by the community care prescriber, demonstrating the CPP’s essential role. Results indicate that most CPP clinical interventions involved clarifying and correcting doses, managing pertinent drug interactions, and ensuring appropriate use of medications according to clinical and national VA guidelines. Other studies have examined the impact of CPPs on patient care and cancer treatment.5,6 The randomized, multicenter AMBORA trial found that clinical pharmacist support reduced severe AEs and medication errors related to oral anticancer agents.5 The per-patient mean number of medication errors found by pharmacist review was 1.7 (range, 0 to 9), with most medication errors noted at the prescribing stage.5 Suzuki and colleagues analyzed data from 35,062 chemotherapy regimens and found that 53.1% of the chemotherapy prescriptions were modified because of pharmacist interventions.6 The most common reason for prescription modifications was prescription error.
Most of the clinical interventions in this study were accepted by community HCPs, indicating that these prescribers are receptive to hematology/oncology CPP input. Among those with no response, most were in relation to recommendations regarding drug interactions. In most of these cases, the drug interaction was not clinically concerning enough to require a response before the CPP approved the prescription. Therefore, it is unknown whether the outside HCP implemented the clinical recommendations. The most common types of clinical interventions the community care HCP declined were dose adjustment requests or requests to switch to a more cost-effective/formulary-preferred agent. In these cases, the prescriber’s preference was documented and, if clinically appropriate, approved by the CPP.
Although the financial implications of CPP clinical interventions were only marginally evaluated in this review, results suggest that cost savings by requests to switch to a cost-effective/formulary preferred agent or prescription denials are substantial. Because of changes in prescription costs over time, it is possible that savings from CPP intervention were greater than calculations using current Federal Supply Schedule Service pricing. The total impact of CPP prescription interventions on reducing or preventing hospitalizations or AEs is not known from this review, but other data suggest that cost savings may benefit the system.13,14
Limitations
This study's retrospective design is a limitation because practice patterns at the VANTHCS involving multiple hematology/oncology CPPs review of community care prescriptions might have evolved over time. The total financial implications of CPP interventions cannot fully be elucidated. The cost of alternative therapies used for patients who received a prescription denial is not factored into this review.
Conclusions
VANTHCS CPPs played an essential role in reviewing anticancer medication prescriptions from community care prescribers. In this study, CPP clinical interventions were completed for more than one-third of the prescriptions and the community-based HCP approved most of these interventions. These changes also resulted in financial benefits.
These findings add to the body of literature emphasizing the need for hematology/oncology-trained CPPs to review anticancer prescriptions and treatment plans. Our review could be used to justify CPP involvement in community care specialty medication review at VA facilities that do not currently have CPP involvement.
The value of a hematology/oncology clinical pharmacy practitioner (CPP) has been validated in several studies documenting their positive impact on patient outcomes, supportive care management, laboratory monitoring, medication error identification, and drug expenditure.1-6 With> 200 oncology-related US Food and Drug Administration approval notifications published from 2020 to 2023, it is no surprise that national trends in oncology drug clinic expenditures increased from $39.9 billion in 2020 to $44.1 billion in 2021.7,8 With the rapidly changing treatment landscape, new drug approvals, and risk of polypharmacy, oral anticancer agents carry a high risk for medication errors.4 Additional challenges include complex dosing regimens and instructions, adherence issues, drug interactions, adjustments for organ dysfunction, and extensive adverse effect (AE) profiles.
Because of the niche and complexity of oral anticancer agents, trained CPPs havehematology/oncology education and expertise that pharmacists without specialized training lack. A survey of 243 nonspecialized community pharmacists that assessed their knowledge of oral anticancer therapies revealed that only about half of the knowledge questions were answered correctly, illustrating an education gap among these pharmacists.9 The Hematology/Oncology Pharmacist Association's suggests that best practices for managing oral oncology therapy should include comprehensive medication review by an oncology-trained pharmacist for each prescription.10
The US Department of Veterans Affairs (VA) community care network, which was established by the MISSION Act, allows covered access for eligible veterans in the local community outside of the VA network. Unfortunately, this dual-system use of health care could increase the risk of poorly coordinated care and has been associated with the risk of inappropriate prescribing.11,12 It is unclear how many private practices enrolled in the community care program have access to oncology-trained pharmacists. Specialized pharmaceutical reviews of oral anticancer medication prescriptions from these practices are vital for veteran care. This study evaluates the clinical and financial interventions of hematology/oncology CPPs review of specialty hematology/oncology prescriptions from community care health care practitioners (HCPs) at the Veterans Affairs North Texas Health Care System (VANTHCS) in Dallas.
METHODS
This study is a retrospective review of Computerized Patient Record System (CPRS) records of patients at VANTHCS from January 1, 2015, to June 30, 2023. Patients included were aged ≥ 18 years, enrolled in the VA community care program, received a specialty hematology/oncology medication that was dispensed through VA pharmacies or VA-contracted pharmacies, and had an hematology/oncology CPP medication review documented in CPRS. The primary aim of this study was to assess the number and types of clinical interventions performed. A clinical intervention was defined as a documented communication attempt with a community care HCP or direct communication with a patient to address a specific medication-related issue noted during CPP review.
Review of specialty hematology/oncology medications by a hematology/oncology CPP included evaluation of therapy indication, such as whether the prescription meets clinical guidelines, VA criteria for use, or other clinical literature as judged appropriate by the CPP. In some cases, the CPP requested that the community care HCP prescribe a more cost-effective or formulary-preferred agent. Each prescription was reviewed for dosage and formulation appropriateness, drug interactions with available medication lists, baseline laboratory test completion, and recommended supportive care medicines. At times, patient counseling is completed as part of the clinical review. When necessary, CPPs could discuss patient cases with a VA-employed oncologist for further oversight regarding appropriateness and safety. Secondary outcomes included the number of interventions accepted or denied by the prescriber provider and cost savings.
Data collected included the type of malignancy, hematology/oncology specialty medication requested, number and type of interventions sent to the community care prescriber, number of interventions accepted or denied by the community care prescriber, and whether the CPP conducted patient counseling or dispensed or denied the product. Cost savings were calculated for medications that were denied or changed to a formulary preferred or cost-effective agent using pricing data from the National Acquisition Center Contract Catalog or Federal Supply Schedule Service as of April 2024.
RESULTS
A total of 221 hematology/oncology prescriptions met inclusion criteria. Among patients receiving these prescriptions, the median age was 70 years and 91% were male. The most common malignancies included 31 instances of multiple myeloma (14%), 26 for chronic lymphocytic leukemia (12%), 24 for prostate cancer (11%), 23 for glioblastoma/brain cancer (10%), 18 for renal cell carcinoma (8%), 17 for colorectal cancer (8%), and 15 for acute myeloid leukemia (7%). Clinical interventions by the hematology/oncology CPP were completed for 82 (37%) of the 221 prescriptions. One clinical intervention was communicated directly to the patient, and attempts were made to communicate with the community care HCP for the remaining 81 prescriptions. The CPP documented 97 clinical interventions for the 82 prescriptions (Table 1). The most commonly documented clinical interventions included: 25 for managing/preventing a drug interaction (26%), 24 for dose adjustment request (25%), 13 for prescription denial (13%), and 11 for requesting the use of a preferred or more cost-effective product (11%). Of note, 16 patients (7%) received counseling from the hematology/oncology CPP. Ten patients (5%) received counseling alone with no other intervention and did not meet the definition of a clinical intervention.
The most frequent prescriptions requiring intervention included 8 for enzalutamide, 7 for venetoclax, 6 for ibrutinib, and 5 each for lenalidomide, cabozantinib, and temozolomide. Among the 97 interventions, 68 were approved (70%), 15 received no response (16%), and 14 were denied by the community care HCP (14%). Despite obtaining no response or intervention denial from the community care HCP, hematology/oncology CPPs could approve these prescriptions if clinically appropriate, and their reasoning was documented. Table 2 further describes the types of interventions that were denied or obtained no response by the community care practitioner. Among the prescriptions denied by the hematology/oncology CPP, 11 were rejected for off-label indications and/or did not have support through primary literature, national guidelines, or VA criteria for use. Only 2 prescriptions were denied for safety concerns.
These documented clinical interventions had financial implications. For drugs with available cost data, requesting the use of a preferred/cost-effective product led to estimated savings of at least $263,536 over the study period with some ongoing cost savings. Prescription denials led to further estimated savings of $186,275 per month, although this is limited by the lack of known costs of alternative therapies the community care physicians chose.
DISCUSSION
More than one-third of prescriptions required clinical interventions, and 70% of these interventions were accepted by the community care prescriber, demonstrating the CPP’s essential role. Results indicate that most CPP clinical interventions involved clarifying and correcting doses, managing pertinent drug interactions, and ensuring appropriate use of medications according to clinical and national VA guidelines. Other studies have examined the impact of CPPs on patient care and cancer treatment.5,6 The randomized, multicenter AMBORA trial found that clinical pharmacist support reduced severe AEs and medication errors related to oral anticancer agents.5 The per-patient mean number of medication errors found by pharmacist review was 1.7 (range, 0 to 9), with most medication errors noted at the prescribing stage.5 Suzuki and colleagues analyzed data from 35,062 chemotherapy regimens and found that 53.1% of the chemotherapy prescriptions were modified because of pharmacist interventions.6 The most common reason for prescription modifications was prescription error.
Most of the clinical interventions in this study were accepted by community HCPs, indicating that these prescribers are receptive to hematology/oncology CPP input. Among those with no response, most were in relation to recommendations regarding drug interactions. In most of these cases, the drug interaction was not clinically concerning enough to require a response before the CPP approved the prescription. Therefore, it is unknown whether the outside HCP implemented the clinical recommendations. The most common types of clinical interventions the community care HCP declined were dose adjustment requests or requests to switch to a more cost-effective/formulary-preferred agent. In these cases, the prescriber’s preference was documented and, if clinically appropriate, approved by the CPP.
Although the financial implications of CPP clinical interventions were only marginally evaluated in this review, results suggest that cost savings by requests to switch to a cost-effective/formulary preferred agent or prescription denials are substantial. Because of changes in prescription costs over time, it is possible that savings from CPP intervention were greater than calculations using current Federal Supply Schedule Service pricing. The total impact of CPP prescription interventions on reducing or preventing hospitalizations or AEs is not known from this review, but other data suggest that cost savings may benefit the system.13,14
Limitations
This study's retrospective design is a limitation because practice patterns at the VANTHCS involving multiple hematology/oncology CPPs review of community care prescriptions might have evolved over time. The total financial implications of CPP interventions cannot fully be elucidated. The cost of alternative therapies used for patients who received a prescription denial is not factored into this review.
Conclusions
VANTHCS CPPs played an essential role in reviewing anticancer medication prescriptions from community care prescribers. In this study, CPP clinical interventions were completed for more than one-third of the prescriptions and the community-based HCP approved most of these interventions. These changes also resulted in financial benefits.
These findings add to the body of literature emphasizing the need for hematology/oncology-trained CPPs to review anticancer prescriptions and treatment plans. Our review could be used to justify CPP involvement in community care specialty medication review at VA facilities that do not currently have CPP involvement.
1. Shah NN, Casella E, Capozzi D, et al. Improving the safety of oral chemotherapy at an academic medical center. J Oncol Pract. 2016;12(1):e71-e76. doi:10.1200/JOP.2015.007260
2. Gatwood J, Gatwood K, Gabre E, Alexander M. Impact of clinical pharmacists in outpatient oncology practices: a review. Am J Health Syst Pharm. 2017;74(19):1549-1557. doi:10.2146/ajhp160475
3. Lankford C, Dura J, Tran A, et al. Effect of clinical pharmacist interventions on cost in an integrated health system specialty pharmacy. J Manag Care Spec Pharm. 2021;27(3):379-384. doi:10.18553/jmcp.2021.27.3.379
4. Schlichtig K, Dürr P, Dörje F, Fromm MF. Medication errors during treatment with new oral anticancer agents: consequences for clinical practice based on the AMBORA Study. Clin Pharmacol Ther. 2021;110(4):1075-1086. doi:10.1002/cpt.2338
5. Dürr P, Schlichtig K, Kelz C, et al. The randomized AMBORA Trial: impact of pharmacological/pharmaceutical care on medication safety and patient-reported outcomes during treatment with new oral anticancer agents. J Clin Oncol. 2021;39(18):1983-1994. doi:10.1200/JCO.20.03088
6. Suzuki S, Chan A, Nomura H, Johnson PE, Endo K, Saito S. Chemotherapy regimen checks performed by pharmacists contribute to safe administration of chemotherapy. J Oncol Pharm Pract. 2017;23(1):18-25. doi:10.1177/1078155215614998
7. Tichy EM, Hoffman JM, Suda KJ, et al. National trends in prescription drug expenditures and projections for 2022. Am J Health Syst Pharm. 2022;79(14):1158-1172. doi:10.1093/ajhp/zxac102
8. US Food and Drug Administration. Oncology (cancer)/hematologic malignancies approval notifications. 2023.
9. O’Bryant CL, Crandell BC. Community pharmacists’ knowledge of and attitudes toward oral chemotherapy. J Am Pharm Assoc (2003). 2008;48(5):632-639. doi:10.1331/JAPhA.2008.07082
10. Mackler E, Segal EM, Muluneh B, Jeffers K, Carmichael J. 2018 hematology/oncology pharmacist association best practices for the management of oral oncolytic therapy: pharmacy practice standard. J Oncol Pract. 2019;15(4):e346-e355. doi:10.1200/JOP.18.00581
11. Thorpe JM, Thorpe CT, Schleiden L, et al. Association between dual use of Department of Veterans Affairs and Medicare part D drug benefits and potentially unsafe prescribing. JAMA Intern Med. 2019;179(11):1584-1586. doi:10.1001/jamainternmed.2019.2788
12. Thorpe JM, Thorpe CT, Gellad WF, et al. Dual health care system use and high-risk prescribing in patients with dementia: a national cohort study. Ann Intern Med. 2017;166(3):157-163. doi:10.7326/M16-0551
13. Chen P-Z, Wu C-C, Huang C-F. Clinical and economic impact of clinical pharmacist intervention in a hematology unit. J Oncol Pharm Pract. 2020;26(4):866-872. doi:10.1177/1078155219875806
14. Dalton K, Byrne S. Role of the pharmacist in reducing healthcare costs: current insights. Integr Pharm Res Pract. 2017;6:37-46. doi:10.2147/IPRP.S108047
1. Shah NN, Casella E, Capozzi D, et al. Improving the safety of oral chemotherapy at an academic medical center. J Oncol Pract. 2016;12(1):e71-e76. doi:10.1200/JOP.2015.007260
2. Gatwood J, Gatwood K, Gabre E, Alexander M. Impact of clinical pharmacists in outpatient oncology practices: a review. Am J Health Syst Pharm. 2017;74(19):1549-1557. doi:10.2146/ajhp160475
3. Lankford C, Dura J, Tran A, et al. Effect of clinical pharmacist interventions on cost in an integrated health system specialty pharmacy. J Manag Care Spec Pharm. 2021;27(3):379-384. doi:10.18553/jmcp.2021.27.3.379
4. Schlichtig K, Dürr P, Dörje F, Fromm MF. Medication errors during treatment with new oral anticancer agents: consequences for clinical practice based on the AMBORA Study. Clin Pharmacol Ther. 2021;110(4):1075-1086. doi:10.1002/cpt.2338
5. Dürr P, Schlichtig K, Kelz C, et al. The randomized AMBORA Trial: impact of pharmacological/pharmaceutical care on medication safety and patient-reported outcomes during treatment with new oral anticancer agents. J Clin Oncol. 2021;39(18):1983-1994. doi:10.1200/JCO.20.03088
6. Suzuki S, Chan A, Nomura H, Johnson PE, Endo K, Saito S. Chemotherapy regimen checks performed by pharmacists contribute to safe administration of chemotherapy. J Oncol Pharm Pract. 2017;23(1):18-25. doi:10.1177/1078155215614998
7. Tichy EM, Hoffman JM, Suda KJ, et al. National trends in prescription drug expenditures and projections for 2022. Am J Health Syst Pharm. 2022;79(14):1158-1172. doi:10.1093/ajhp/zxac102
8. US Food and Drug Administration. Oncology (cancer)/hematologic malignancies approval notifications. 2023.
9. O’Bryant CL, Crandell BC. Community pharmacists’ knowledge of and attitudes toward oral chemotherapy. J Am Pharm Assoc (2003). 2008;48(5):632-639. doi:10.1331/JAPhA.2008.07082
10. Mackler E, Segal EM, Muluneh B, Jeffers K, Carmichael J. 2018 hematology/oncology pharmacist association best practices for the management of oral oncolytic therapy: pharmacy practice standard. J Oncol Pract. 2019;15(4):e346-e355. doi:10.1200/JOP.18.00581
11. Thorpe JM, Thorpe CT, Schleiden L, et al. Association between dual use of Department of Veterans Affairs and Medicare part D drug benefits and potentially unsafe prescribing. JAMA Intern Med. 2019;179(11):1584-1586. doi:10.1001/jamainternmed.2019.2788
12. Thorpe JM, Thorpe CT, Gellad WF, et al. Dual health care system use and high-risk prescribing in patients with dementia: a national cohort study. Ann Intern Med. 2017;166(3):157-163. doi:10.7326/M16-0551
13. Chen P-Z, Wu C-C, Huang C-F. Clinical and economic impact of clinical pharmacist intervention in a hematology unit. J Oncol Pharm Pract. 2020;26(4):866-872. doi:10.1177/1078155219875806
14. Dalton K, Byrne S. Role of the pharmacist in reducing healthcare costs: current insights. Integr Pharm Res Pract. 2017;6:37-46. doi:10.2147/IPRP.S108047
Several Skin Conditions More Likely in Children With Obesity
TORONTO — results of new research show.
The retrospective cohort study found markedly higher rates of skin infections, atopic dermatitis (AD), and acanthosis nigricans among children with overweight, compared with children with average weight.
“Many conditions associated with obesity are strong predictors of cardiovascular mortality as these children age, so doctors can play a key role in advocating for weight loss strategies in this population,” lead study author Samantha Epstein, third-year medical student at Case Western Reserve University, Cleveland, Ohio, said in an interview. The findings were presented at the annual meeting of the Society for Pediatric Dermatology.
Previous research has linked obesity, a chronic inflammatory condition, to psoriasis, AD, hidradenitis suppurativa (HS), acne vulgaris, infections, and rosacea in adults. However, there’s scant research exploring the connection between obesity and cutaneous conditions in children.
According to the Cleveland Clinic, childhood obesity is defined as a body mass index, which is weight in kg divided by the square of height in m2, at or above the 95th percentile for age and sex in children aged 2 years or older.
For the study, Ms. Epstein and coauthor Sonal D. Shah, MD, associate professor, Department of Dermatology, Case Western Reserve University, and a board-certified pediatric dermatologist accessed a large national research database and used diagnostic codes to identify over 1 million children (mean age, 8.5 years). Most (about 44%) were White; about one-quarter were Black. The groups were propensity matched, so there were about equal numbers of youngsters with and without obesity and of boys and girls.
They collected data on AD, HS, rosacea, psoriasis, and acanthosis nigricans (a thickened purplish discoloration typically found in body folds around the armpits, groin, and neck). They also gathered information on comorbidities.
Acanthosis nigricans, which is linked to metabolic syndrome, type 2 diabetes, and insulin resistance , was more prevalent among children with obesity (20,885 cases in the with-obesity group and 336 in the without-obesity group, for a relative risk [RR] of 62.16 and an odds ratio [OR] of 64.38).
Skin and subcutaneous tissue infections were also more common among those with obesity (14,795 cases) vs 4720 cases among those without obesity (RR, 3.14; OR, 3.2). As for AD, there were 11,892 cases in the with-obesity group and 2983 in the without-obesity group (RR, 3.99; OR, 4.06). There were 1166 cases of psoriasis among those with obesity and 408 among those without obesity (RR, 2.86; OR, 2.88).
HS (587 cases in the with-obesity group and 70 in the without-obesity group; RR, 8.39; OR, 8.39) and rosacea (351 in the with-obesity group and 138 in the without-obesity group; RR, 2.54; OR, 2.55) were the least common skin conditions.
Higher Comorbidity Rates
Compared with their average-weight counterparts, the children with obesity had higher rates of comorbidities, including type 2 diabetes. Ms. Epstein noted that children with diabetes and obesity had increased risks for every skin condition except for infections of the skin and subcutaneous tissue when compared with children without obesity.
Such infections were the most common skin conditions among children without obesity. “This was expected just due to the fact that children are outside, they’re playing in the grass and the dirt, and they get infected,” said Ms. Epstein. Still, these infections were three times more common in youngsters with obesity.
Although acanthosis nigricans is “highly correlated” with type 2 diabetes, “not as many children as we would expect in this population have developed type 2 diabetes,” said Ms. Epstein. This might make some sense, though, because these children are still quite young. “When dermatologists recognize this skin condition, they can advocate for weight loss management to try to prevent it.”
Other conditions seen more often in the overweight children with overweight included: hypertension, hyperlipidemia, obstructive sleep apnea, polycystic ovarian syndrome, attention-deficit/hyperactivity disorder, major depressive disorder, depressive episodes, and anxiety (all P < .001).
Commenting on the results, Sonia Havele, MD, a pediatrician and dermatology resident at Children’s Mercy Hospital, Kansas City, Missouri, said in an interview that the study reflects trends that she and her colleagues see in clinic: There are more common skin conditions in their patients with obesity.
She agreed that it offers an opening for education. “The results of this study highlight the opportunity we have as pediatric dermatologists to provide additional counseling on obesity and offer referrals to our colleagues in endocrinology, gastroenterology, and nutrition if needed.”
No conflicts of interest were reported.
TORONTO — results of new research show.
The retrospective cohort study found markedly higher rates of skin infections, atopic dermatitis (AD), and acanthosis nigricans among children with overweight, compared with children with average weight.
“Many conditions associated with obesity are strong predictors of cardiovascular mortality as these children age, so doctors can play a key role in advocating for weight loss strategies in this population,” lead study author Samantha Epstein, third-year medical student at Case Western Reserve University, Cleveland, Ohio, said in an interview. The findings were presented at the annual meeting of the Society for Pediatric Dermatology.
Previous research has linked obesity, a chronic inflammatory condition, to psoriasis, AD, hidradenitis suppurativa (HS), acne vulgaris, infections, and rosacea in adults. However, there’s scant research exploring the connection between obesity and cutaneous conditions in children.
According to the Cleveland Clinic, childhood obesity is defined as a body mass index, which is weight in kg divided by the square of height in m2, at or above the 95th percentile for age and sex in children aged 2 years or older.
For the study, Ms. Epstein and coauthor Sonal D. Shah, MD, associate professor, Department of Dermatology, Case Western Reserve University, and a board-certified pediatric dermatologist accessed a large national research database and used diagnostic codes to identify over 1 million children (mean age, 8.5 years). Most (about 44%) were White; about one-quarter were Black. The groups were propensity matched, so there were about equal numbers of youngsters with and without obesity and of boys and girls.
They collected data on AD, HS, rosacea, psoriasis, and acanthosis nigricans (a thickened purplish discoloration typically found in body folds around the armpits, groin, and neck). They also gathered information on comorbidities.
Acanthosis nigricans, which is linked to metabolic syndrome, type 2 diabetes, and insulin resistance , was more prevalent among children with obesity (20,885 cases in the with-obesity group and 336 in the without-obesity group, for a relative risk [RR] of 62.16 and an odds ratio [OR] of 64.38).
Skin and subcutaneous tissue infections were also more common among those with obesity (14,795 cases) vs 4720 cases among those without obesity (RR, 3.14; OR, 3.2). As for AD, there were 11,892 cases in the with-obesity group and 2983 in the without-obesity group (RR, 3.99; OR, 4.06). There were 1166 cases of psoriasis among those with obesity and 408 among those without obesity (RR, 2.86; OR, 2.88).
HS (587 cases in the with-obesity group and 70 in the without-obesity group; RR, 8.39; OR, 8.39) and rosacea (351 in the with-obesity group and 138 in the without-obesity group; RR, 2.54; OR, 2.55) were the least common skin conditions.
Higher Comorbidity Rates
Compared with their average-weight counterparts, the children with obesity had higher rates of comorbidities, including type 2 diabetes. Ms. Epstein noted that children with diabetes and obesity had increased risks for every skin condition except for infections of the skin and subcutaneous tissue when compared with children without obesity.
Such infections were the most common skin conditions among children without obesity. “This was expected just due to the fact that children are outside, they’re playing in the grass and the dirt, and they get infected,” said Ms. Epstein. Still, these infections were three times more common in youngsters with obesity.
Although acanthosis nigricans is “highly correlated” with type 2 diabetes, “not as many children as we would expect in this population have developed type 2 diabetes,” said Ms. Epstein. This might make some sense, though, because these children are still quite young. “When dermatologists recognize this skin condition, they can advocate for weight loss management to try to prevent it.”
Other conditions seen more often in the overweight children with overweight included: hypertension, hyperlipidemia, obstructive sleep apnea, polycystic ovarian syndrome, attention-deficit/hyperactivity disorder, major depressive disorder, depressive episodes, and anxiety (all P < .001).
Commenting on the results, Sonia Havele, MD, a pediatrician and dermatology resident at Children’s Mercy Hospital, Kansas City, Missouri, said in an interview that the study reflects trends that she and her colleagues see in clinic: There are more common skin conditions in their patients with obesity.
She agreed that it offers an opening for education. “The results of this study highlight the opportunity we have as pediatric dermatologists to provide additional counseling on obesity and offer referrals to our colleagues in endocrinology, gastroenterology, and nutrition if needed.”
No conflicts of interest were reported.
TORONTO — results of new research show.
The retrospective cohort study found markedly higher rates of skin infections, atopic dermatitis (AD), and acanthosis nigricans among children with overweight, compared with children with average weight.
“Many conditions associated with obesity are strong predictors of cardiovascular mortality as these children age, so doctors can play a key role in advocating for weight loss strategies in this population,” lead study author Samantha Epstein, third-year medical student at Case Western Reserve University, Cleveland, Ohio, said in an interview. The findings were presented at the annual meeting of the Society for Pediatric Dermatology.
Previous research has linked obesity, a chronic inflammatory condition, to psoriasis, AD, hidradenitis suppurativa (HS), acne vulgaris, infections, and rosacea in adults. However, there’s scant research exploring the connection between obesity and cutaneous conditions in children.
According to the Cleveland Clinic, childhood obesity is defined as a body mass index, which is weight in kg divided by the square of height in m2, at or above the 95th percentile for age and sex in children aged 2 years or older.
For the study, Ms. Epstein and coauthor Sonal D. Shah, MD, associate professor, Department of Dermatology, Case Western Reserve University, and a board-certified pediatric dermatologist accessed a large national research database and used diagnostic codes to identify over 1 million children (mean age, 8.5 years). Most (about 44%) were White; about one-quarter were Black. The groups were propensity matched, so there were about equal numbers of youngsters with and without obesity and of boys and girls.
They collected data on AD, HS, rosacea, psoriasis, and acanthosis nigricans (a thickened purplish discoloration typically found in body folds around the armpits, groin, and neck). They also gathered information on comorbidities.
Acanthosis nigricans, which is linked to metabolic syndrome, type 2 diabetes, and insulin resistance , was more prevalent among children with obesity (20,885 cases in the with-obesity group and 336 in the without-obesity group, for a relative risk [RR] of 62.16 and an odds ratio [OR] of 64.38).
Skin and subcutaneous tissue infections were also more common among those with obesity (14,795 cases) vs 4720 cases among those without obesity (RR, 3.14; OR, 3.2). As for AD, there were 11,892 cases in the with-obesity group and 2983 in the without-obesity group (RR, 3.99; OR, 4.06). There were 1166 cases of psoriasis among those with obesity and 408 among those without obesity (RR, 2.86; OR, 2.88).
HS (587 cases in the with-obesity group and 70 in the without-obesity group; RR, 8.39; OR, 8.39) and rosacea (351 in the with-obesity group and 138 in the without-obesity group; RR, 2.54; OR, 2.55) were the least common skin conditions.
Higher Comorbidity Rates
Compared with their average-weight counterparts, the children with obesity had higher rates of comorbidities, including type 2 diabetes. Ms. Epstein noted that children with diabetes and obesity had increased risks for every skin condition except for infections of the skin and subcutaneous tissue when compared with children without obesity.
Such infections were the most common skin conditions among children without obesity. “This was expected just due to the fact that children are outside, they’re playing in the grass and the dirt, and they get infected,” said Ms. Epstein. Still, these infections were three times more common in youngsters with obesity.
Although acanthosis nigricans is “highly correlated” with type 2 diabetes, “not as many children as we would expect in this population have developed type 2 diabetes,” said Ms. Epstein. This might make some sense, though, because these children are still quite young. “When dermatologists recognize this skin condition, they can advocate for weight loss management to try to prevent it.”
Other conditions seen more often in the overweight children with overweight included: hypertension, hyperlipidemia, obstructive sleep apnea, polycystic ovarian syndrome, attention-deficit/hyperactivity disorder, major depressive disorder, depressive episodes, and anxiety (all P < .001).
Commenting on the results, Sonia Havele, MD, a pediatrician and dermatology resident at Children’s Mercy Hospital, Kansas City, Missouri, said in an interview that the study reflects trends that she and her colleagues see in clinic: There are more common skin conditions in their patients with obesity.
She agreed that it offers an opening for education. “The results of this study highlight the opportunity we have as pediatric dermatologists to provide additional counseling on obesity and offer referrals to our colleagues in endocrinology, gastroenterology, and nutrition if needed.”
No conflicts of interest were reported.
FROM SPD 2024
Generalized Fixed Drug Eruptions Require Urgent Care: A Case Series
Recognizing cutaneous drug eruptions is important for treatment and prevention of recurrence. Fixed drug eruptions (FDEs) typically are harmless but can have major negative cosmetic consequences for patients. In its more severe forms, patients are at risk for widespread epithelial necrosis with accompanying complications. We report 1 patient with generalized FDE and 2 with generalized bullous FDE. We also discuss the recognition and treatment of the condition. Two patients previously had been diagnosed with systemic lupus erythematosus (SLE).
Case Series
Patient 1—A 60-year-old woman presented to dermatology with a rash on the trunk and groin folds of 4 days’ duration. She had a history of SLE and cutaneous lupus treated with hydroxychloroquine 200 mg twice daily and topical corticosteroids. She had started sulfamethoxazole-trimethoprim for a urinary tract infection with a rash appearing 1 day later. She reported burning skin pain with progression to blisters that “sloughed” off. She denied any known history of allergy to sulfa drugs. Prior to evaluation by dermatology, she visited an urgent care facility and was prescribed hydroxyzine and intramuscular corticosteroids. At presentation to dermatology 3 days after taking sulfamethoxazole-trimethoprim, she had annular flaccid bullae and superficial erosions with dusky borders on the right posterior thigh, right side of the chest, left inframammary fold, and right inguinal fold (Figure 1). She had no ocular, oral, or vaginal erosions. A diagnosis of generalized bullous FDE was favored over erythema multiforme or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Shave biopsies from lesions on the right posterior thigh and right inguinal fold demonstrated interface dermatitis with epidermal necrosis, pigment incontinence, and numerous eosinophils. Direct immunofluorescence of the perilesional skin was negative for immunoprotein deposition. These findings were consistent with the clinical impression of generalized bullous FDE. Prior to receiving the histopathology report, the patient was initiated on a regimen of cyclosporine 5 mg/kg/d in the setting of normal renal function and followed until the eruption resolved completely. Cyclosporine was tapered at 2 weeks and discontinued at 3 weeks.
Patient 2—A 32-year-old woman presented for follow-up management of discoid lupus erythematosus. She had a history of systemic and cutaneous lupus, juvenile rheumatoid arthritis, and mixed connective tissue disease managed with prednisone, hydroxychloroquine, azathioprine, and belimumab. Physical examination revealed scarring alopecia with dyspigmentation and active inflammation consistent with uncontrolled cutaneous lupus. However, she also had oval-shaped hyperpigmented patches over the left breast, clavicle, and anterior chest consistent with a generalized FDE (Figure 2). The patient did not recall a history of similar lesions and could not identify a possible trigger. She was counseled on possible culprits and advised to avoid unnecessary medications. She had an unremarkable clinical course; therefore, no further intervention was necessary.
Patient 3—A 33-year-old man presented to the emergency department with a painful rash on the chest and back of 2 days’ duration that began 1 hour after taking naproxen (dosage unknown) for back pain. He had no notable medical history. The patient stated that the rash had slowly worsened and started to develop blisters. He visited an urgent care facility 1 day prior to the current presentation and was started on a 5-day course of prednisone 40 mg daily; the first 2 doses did not help. He denied any mucosal involvement apart from a tender lesion on the penis. He reported a history of an allergic reaction to penicillin. Physical examination revealed extensive dusky violaceous annular plaques with erythematous borders across the anterior and posterior trunk (Figure 3). Multiple flaccid bullae developed within these plaques, involving 15% of the body surface area. He was diagnosed with generalized bullous FDE based on the clinical history and histopathology. He was admitted to the burn intensive care unit and treated with cyclosporine 3 mg/kg/d with subsequent resolution of the eruption.
Comment
Presentation of FDEs—A fixed drug eruption manifests with 1 or more well-demarcated, red or violaceous, annular patches that resolve with postinflammatory hyperpigmentation; it occasionally may manifest with bullae. Initial eruptions may occur up to 2 weeks following medication exposure, but recurrent eruptions usually happen within minutes to hours later. They often are in the same location as prior lesions. A fixed drug eruption can be solitary, scattered, or generalized; a generalized FDE typically demonstrates multiple bilateral lesions that may itch, burn, or cause no symptoms. Patients can experience an FDE at any age, though the median age is reported as 35 to 60 years of age.1 A fixed drug eruption usually occurs after ingestion of oral medications, though there have been a few reports with iodinated contrast.2 Well-known culprits include antibiotics (eg, sulfamethoxazole-trimethoprim, tetracyclines, penicillins/cephalosporins, quinolones, dapsone), nonsteroidal anti-inflammatory drugs, acetaminophen (eg, paracetamol), barbiturates, antimalarials, and anticonvulsants. It also can occur with vaccines or with certain foods (fixed food eruption).3,4 Clinicians may try an oral drug challenge to identify the cause of an FDE, but in patients with a history of a generalized FDE, the risk for developing an increasingly severe reaction with repeated exposure to the medication is too high.5
Histopathology—Patch testing at the site of prior eruption with suspected drug culprits may be useful.6 Histopathology of FDE typically demonstrates vacuolar changes at the dermoepidermal junction with a lichenoid lymphocytic infiltrate. Early lesions often show a predominance of eosinophils. Subepidermal clefting is a feature of the bullous variant. In an active lesion, there are large numbers of CD8+ T lymphocytes expressing natural killer cell–associated molecules.7 The pathologic mechanism is not well understood, though it has been hypothesized that memory CD8+ cells are maintained in specific regions of the epidermis by IL-15 produced in the microenvironment and are activated upon rechallenge.7Considerations in Generalized Bullous FDE—Generalized FDE is defined in the literature as an FDE with involvement of 3 of 6 body areas: head, neck, trunk, upper limbs, lower limbs, and genital area. It may cover more or less than 10% of the body surface area.8-10 Although an isolated FDE frequently is asymptomatic and may not be cause for alarm, recurring drug eruptions increase the risk for development of generalized bullous FDE. Generalized bullous FDE is a rare subset. It is frequently misdiagnosed, and data on its incidence are uncertain.11 Of note, several pathologies causing bullous lesions may be in the differential diagnosis, including bullous pemphigoid; pemphigus vulgaris; bullous SLE; or bullae from cutaneous lupus, staphylococcal scalded skin syndrome, erythema multiforme, or SJS/TEN.12 When matched for body surface area involvement with SJS/TEN, generalized bullous FDE shares nearly identical mortality rates10; therefore, these patients should be treated with the same level of urgency and admitted to a critical care or burn unit, as they are at serious risk for infection and other complications.13
Clinical history and presentation along with histopathologic findings help to narrow down the differential diagnosis. Clinically, generalized bullous FDE does not affect the surrounding skin and manifests sooner after drug exposure (1–24 hours) with less mucosal involvement than SJS/TEN.9 Additionally, SJS/TEN patients frequently have generalized malaise and/or fever, while generalized bullous FDE patients do not. Finally, patients with generalized bullous FDE may report a history of a cutaneous eruption similar in morphology or in the same location.
Histopathologically, generalized bullous FDE may be similar to FDE with the addition of a subepidermal blister. Generalized bullous FDE patients have greater eosinophil infiltration and dermal melanophages than patients with SJS/TEN.9 Cellular infiltrates in generalized bullous FDE include more dermal CD41 cells, such as Foxp31 regulatory T cells; fewer intraepidermal CD561 cells; and fewer intraepidermal cells with granulysin.9 Occasionally, generalized bullous FDE causes full-thickness necrosis. In those cases, generalized bullous FDE cannot reliably be distinguished from other conditions with epidermal necrolysis on histopathology.13
FDE Diagnostics—A cytotoxin produced by
Management—Avoidance of the inciting drug often is sufficient for patients with an FDE, as demonstrated in patient 2 in our case series. Clinicians also should counsel patients on avoidance of potential cross-reacting drugs. Symptomatic treatment for itch or pain is appropriate and may include antihistamines or topical steroids. Nonsteroidal anti-inflammatory drugs may exacerbate or be causative of FDE. For generalized bullous FDE, cyclosporine is favored in the literature15,16 and was used to successfully treat both patients 1 and 3 in our case series. A short course of systemic corticosteroids or intravenous immunoglobulin also may be considered. Mild cases of generalized bullous FDE may be treated with close outpatient follow-up (patient 1), while severe cases require inpatient or even critical care monitoring with aggressive medical management to prevent the progression of skin desquamation (patient 3). Patients with severe oral lesions may require inpatient support for fluid maintenance.
Lupus History—Two patients in our case series had a history of lupus. Lupus itself can cause primary bullous lesions. Similar to FDE, bullous SLE can involve sun-exposed and nonexposed areas of the skin as well as the mucous membranes with a predilection for the lower vermilion lip.17 In bullous SLE, tense subepidermal blisters with a neutrophil-rich infiltrate form due to circulating antibodies to type VII collagen. These blisters have an erythematous or urticated base, most commonly on the face, upper trunk, and proximal extremities.18 In both SLE with skin manifestations and lupus limited to the skin, bullae may form due to extensive vacuolar degeneration. Similar to TEN, they can form rapidly in a widespread distribution.17 However, there is limited mucosal involvement, no clear drug association, and a better prognosis. Bullae caused by lupus will frequently demonstrate deposition of immunoproteins IgG, IgM, IgA, and complement component 3 at the basement membrane zone in perilesional skin on direct immunofluorescence. However, negative direct immunofluorescence does not rule out lupus.12 At the same time, patients with lupus frequently have comorbidities requiring multiple medications; the need for these medications may predispose patients to higher rates of cutaneous drug eruptions.19 To our knowledge, there is no known association between FDE and lupus.
Conclusion
Patients with acute eruptions following the initiation of a new prescription or over-the-counter medication require urgent evaluation. Generalized bullous FDE requires timely diagnosis and intervention. Patients with lupus have an increased risk for cutaneous drug eruptions due to polypharmacy. Further investigation is necessary to determine if there is a pathophysiologic mechanism responsible for the development of FDE in lupus patients.
- Anderson HJ, Lee JB. A review of fixed drug eruption with a special focus on generalized bullous fixed drug eruption. Medicina (Kaunas). 2021;57:925.
- Gavin M, Sharp L, Walker K, et al. Contrast-induced generalized bullous fixed drug eruption resembling Stevens-Johnson syndrome. Proc (Bayl Univ Med Cent). 2019;32:601-602.
- Kabir S, Feit EJ, Heilman ER. Generalized fixed drug eruption following Pfizer-BioNtech COVID-19 vaccination. Clin Case Rep. 2022;10:E6684.
- Choi S, Kim SH, Hwang JH, et al. Rapidly progressing generalized bullous fixed drug eruption after the first dose of COVID-19 messenger RNA vaccination. J Dermatol. 2023;50:1190-1193.
- Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;37:833-838.
- Shiohara T. Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol. 2009;9:316-321.
- Mizukawa Y, Yamazaki Y, Shiohara T. In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Br J Dermatol. 2008;158:1230-1238.
- Lee CH, Chen YC, Cho YT, et al. Fixed-drug eruption: a retrospective study in a single referral center in northern Taiwan. Dermatologica Sinica. 2012;30:11-15.
- Cho YT, Lin JW, Chen YC, et al. Generalized bullous fixed drug eruption is distinct from Stevens-Johnson syndrome/toxic epidermal necrolysis by immunohistopathological features. J Am Acad Dermatol. 2014;70:539-548.
- Lipowicz S, Sekula P, Ingen-Housz-Oro S, et al. Prognosis of generalized bullous fixed drug eruption: comparison with Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 2013;168:726-732.
- Patel S, John AM, Handler MZ, et al. Fixed drug eruptions: an update, emphasizing the potentially lethal generalized bullous fixed drug eruption. Am J Clin Dermatol. 2020;21:393-399.
- Ranario JS, Smith JL. Bullous lesions in a patient with systemic lupus erythematosus. J Clin Aesthet Dermatol. 2014;7:44-49.
- Perron E, Viarnaud A, Marciano L, et al. Clinical and histological features of fixed drug eruption: a single-centre series of 73 cases with comparison between bullous and non-bullous forms. Eur J Dermatol. 2021;31:372-380.
- Chen CB, Kuo KL, Wang CW, et al. Detecting lesional granulysin levels for rapid diagnosis of cytotoxic T lymphocyte-mediated bullous skin disorders. J Allergy Clin Immunol Pract. 2021;9:1327-1337.e3.
- Beniwal R, Gupta LK, Khare AK, et al. Cyclosporine in generalized bullous-fixed drug eruption. Indian J Dermatol. 2018;63:432-433.
- Vargas Mora P, García S, Valenzuela F, et al. Generalized bullous fixed drug eruption successfully treated with cyclosporine. Dermatol Ther. 2020;33:E13492.
- Montagnon CM, Tolkachjov SN, Murrell DF, et al. Subepithelial autoimmune blistering dermatoses: clinical features and diagnosis. J Am Acad Dermatol. 2021;85:1-14.
- Sebaratnam DF, Murrell DF. Bullous systemic lupus erythematosus. Dermatol Clin. 2011;29:649-653.
- Zonzits E, Aberer W, Tappeiner G. Drug eruptions from mesna. After cyclophosphamide treatment of patients with systemic lupus erythematosus and dermatomyositis. Arch Dermatol. 1992;128:80-82.
Recognizing cutaneous drug eruptions is important for treatment and prevention of recurrence. Fixed drug eruptions (FDEs) typically are harmless but can have major negative cosmetic consequences for patients. In its more severe forms, patients are at risk for widespread epithelial necrosis with accompanying complications. We report 1 patient with generalized FDE and 2 with generalized bullous FDE. We also discuss the recognition and treatment of the condition. Two patients previously had been diagnosed with systemic lupus erythematosus (SLE).
Case Series
Patient 1—A 60-year-old woman presented to dermatology with a rash on the trunk and groin folds of 4 days’ duration. She had a history of SLE and cutaneous lupus treated with hydroxychloroquine 200 mg twice daily and topical corticosteroids. She had started sulfamethoxazole-trimethoprim for a urinary tract infection with a rash appearing 1 day later. She reported burning skin pain with progression to blisters that “sloughed” off. She denied any known history of allergy to sulfa drugs. Prior to evaluation by dermatology, she visited an urgent care facility and was prescribed hydroxyzine and intramuscular corticosteroids. At presentation to dermatology 3 days after taking sulfamethoxazole-trimethoprim, she had annular flaccid bullae and superficial erosions with dusky borders on the right posterior thigh, right side of the chest, left inframammary fold, and right inguinal fold (Figure 1). She had no ocular, oral, or vaginal erosions. A diagnosis of generalized bullous FDE was favored over erythema multiforme or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Shave biopsies from lesions on the right posterior thigh and right inguinal fold demonstrated interface dermatitis with epidermal necrosis, pigment incontinence, and numerous eosinophils. Direct immunofluorescence of the perilesional skin was negative for immunoprotein deposition. These findings were consistent with the clinical impression of generalized bullous FDE. Prior to receiving the histopathology report, the patient was initiated on a regimen of cyclosporine 5 mg/kg/d in the setting of normal renal function and followed until the eruption resolved completely. Cyclosporine was tapered at 2 weeks and discontinued at 3 weeks.
Patient 2—A 32-year-old woman presented for follow-up management of discoid lupus erythematosus. She had a history of systemic and cutaneous lupus, juvenile rheumatoid arthritis, and mixed connective tissue disease managed with prednisone, hydroxychloroquine, azathioprine, and belimumab. Physical examination revealed scarring alopecia with dyspigmentation and active inflammation consistent with uncontrolled cutaneous lupus. However, she also had oval-shaped hyperpigmented patches over the left breast, clavicle, and anterior chest consistent with a generalized FDE (Figure 2). The patient did not recall a history of similar lesions and could not identify a possible trigger. She was counseled on possible culprits and advised to avoid unnecessary medications. She had an unremarkable clinical course; therefore, no further intervention was necessary.
Patient 3—A 33-year-old man presented to the emergency department with a painful rash on the chest and back of 2 days’ duration that began 1 hour after taking naproxen (dosage unknown) for back pain. He had no notable medical history. The patient stated that the rash had slowly worsened and started to develop blisters. He visited an urgent care facility 1 day prior to the current presentation and was started on a 5-day course of prednisone 40 mg daily; the first 2 doses did not help. He denied any mucosal involvement apart from a tender lesion on the penis. He reported a history of an allergic reaction to penicillin. Physical examination revealed extensive dusky violaceous annular plaques with erythematous borders across the anterior and posterior trunk (Figure 3). Multiple flaccid bullae developed within these plaques, involving 15% of the body surface area. He was diagnosed with generalized bullous FDE based on the clinical history and histopathology. He was admitted to the burn intensive care unit and treated with cyclosporine 3 mg/kg/d with subsequent resolution of the eruption.
Comment
Presentation of FDEs—A fixed drug eruption manifests with 1 or more well-demarcated, red or violaceous, annular patches that resolve with postinflammatory hyperpigmentation; it occasionally may manifest with bullae. Initial eruptions may occur up to 2 weeks following medication exposure, but recurrent eruptions usually happen within minutes to hours later. They often are in the same location as prior lesions. A fixed drug eruption can be solitary, scattered, or generalized; a generalized FDE typically demonstrates multiple bilateral lesions that may itch, burn, or cause no symptoms. Patients can experience an FDE at any age, though the median age is reported as 35 to 60 years of age.1 A fixed drug eruption usually occurs after ingestion of oral medications, though there have been a few reports with iodinated contrast.2 Well-known culprits include antibiotics (eg, sulfamethoxazole-trimethoprim, tetracyclines, penicillins/cephalosporins, quinolones, dapsone), nonsteroidal anti-inflammatory drugs, acetaminophen (eg, paracetamol), barbiturates, antimalarials, and anticonvulsants. It also can occur with vaccines or with certain foods (fixed food eruption).3,4 Clinicians may try an oral drug challenge to identify the cause of an FDE, but in patients with a history of a generalized FDE, the risk for developing an increasingly severe reaction with repeated exposure to the medication is too high.5
Histopathology—Patch testing at the site of prior eruption with suspected drug culprits may be useful.6 Histopathology of FDE typically demonstrates vacuolar changes at the dermoepidermal junction with a lichenoid lymphocytic infiltrate. Early lesions often show a predominance of eosinophils. Subepidermal clefting is a feature of the bullous variant. In an active lesion, there are large numbers of CD8+ T lymphocytes expressing natural killer cell–associated molecules.7 The pathologic mechanism is not well understood, though it has been hypothesized that memory CD8+ cells are maintained in specific regions of the epidermis by IL-15 produced in the microenvironment and are activated upon rechallenge.7Considerations in Generalized Bullous FDE—Generalized FDE is defined in the literature as an FDE with involvement of 3 of 6 body areas: head, neck, trunk, upper limbs, lower limbs, and genital area. It may cover more or less than 10% of the body surface area.8-10 Although an isolated FDE frequently is asymptomatic and may not be cause for alarm, recurring drug eruptions increase the risk for development of generalized bullous FDE. Generalized bullous FDE is a rare subset. It is frequently misdiagnosed, and data on its incidence are uncertain.11 Of note, several pathologies causing bullous lesions may be in the differential diagnosis, including bullous pemphigoid; pemphigus vulgaris; bullous SLE; or bullae from cutaneous lupus, staphylococcal scalded skin syndrome, erythema multiforme, or SJS/TEN.12 When matched for body surface area involvement with SJS/TEN, generalized bullous FDE shares nearly identical mortality rates10; therefore, these patients should be treated with the same level of urgency and admitted to a critical care or burn unit, as they are at serious risk for infection and other complications.13
Clinical history and presentation along with histopathologic findings help to narrow down the differential diagnosis. Clinically, generalized bullous FDE does not affect the surrounding skin and manifests sooner after drug exposure (1–24 hours) with less mucosal involvement than SJS/TEN.9 Additionally, SJS/TEN patients frequently have generalized malaise and/or fever, while generalized bullous FDE patients do not. Finally, patients with generalized bullous FDE may report a history of a cutaneous eruption similar in morphology or in the same location.
Histopathologically, generalized bullous FDE may be similar to FDE with the addition of a subepidermal blister. Generalized bullous FDE patients have greater eosinophil infiltration and dermal melanophages than patients with SJS/TEN.9 Cellular infiltrates in generalized bullous FDE include more dermal CD41 cells, such as Foxp31 regulatory T cells; fewer intraepidermal CD561 cells; and fewer intraepidermal cells with granulysin.9 Occasionally, generalized bullous FDE causes full-thickness necrosis. In those cases, generalized bullous FDE cannot reliably be distinguished from other conditions with epidermal necrolysis on histopathology.13
FDE Diagnostics—A cytotoxin produced by
Management—Avoidance of the inciting drug often is sufficient for patients with an FDE, as demonstrated in patient 2 in our case series. Clinicians also should counsel patients on avoidance of potential cross-reacting drugs. Symptomatic treatment for itch or pain is appropriate and may include antihistamines or topical steroids. Nonsteroidal anti-inflammatory drugs may exacerbate or be causative of FDE. For generalized bullous FDE, cyclosporine is favored in the literature15,16 and was used to successfully treat both patients 1 and 3 in our case series. A short course of systemic corticosteroids or intravenous immunoglobulin also may be considered. Mild cases of generalized bullous FDE may be treated with close outpatient follow-up (patient 1), while severe cases require inpatient or even critical care monitoring with aggressive medical management to prevent the progression of skin desquamation (patient 3). Patients with severe oral lesions may require inpatient support for fluid maintenance.
Lupus History—Two patients in our case series had a history of lupus. Lupus itself can cause primary bullous lesions. Similar to FDE, bullous SLE can involve sun-exposed and nonexposed areas of the skin as well as the mucous membranes with a predilection for the lower vermilion lip.17 In bullous SLE, tense subepidermal blisters with a neutrophil-rich infiltrate form due to circulating antibodies to type VII collagen. These blisters have an erythematous or urticated base, most commonly on the face, upper trunk, and proximal extremities.18 In both SLE with skin manifestations and lupus limited to the skin, bullae may form due to extensive vacuolar degeneration. Similar to TEN, they can form rapidly in a widespread distribution.17 However, there is limited mucosal involvement, no clear drug association, and a better prognosis. Bullae caused by lupus will frequently demonstrate deposition of immunoproteins IgG, IgM, IgA, and complement component 3 at the basement membrane zone in perilesional skin on direct immunofluorescence. However, negative direct immunofluorescence does not rule out lupus.12 At the same time, patients with lupus frequently have comorbidities requiring multiple medications; the need for these medications may predispose patients to higher rates of cutaneous drug eruptions.19 To our knowledge, there is no known association between FDE and lupus.
Conclusion
Patients with acute eruptions following the initiation of a new prescription or over-the-counter medication require urgent evaluation. Generalized bullous FDE requires timely diagnosis and intervention. Patients with lupus have an increased risk for cutaneous drug eruptions due to polypharmacy. Further investigation is necessary to determine if there is a pathophysiologic mechanism responsible for the development of FDE in lupus patients.
Recognizing cutaneous drug eruptions is important for treatment and prevention of recurrence. Fixed drug eruptions (FDEs) typically are harmless but can have major negative cosmetic consequences for patients. In its more severe forms, patients are at risk for widespread epithelial necrosis with accompanying complications. We report 1 patient with generalized FDE and 2 with generalized bullous FDE. We also discuss the recognition and treatment of the condition. Two patients previously had been diagnosed with systemic lupus erythematosus (SLE).
Case Series
Patient 1—A 60-year-old woman presented to dermatology with a rash on the trunk and groin folds of 4 days’ duration. She had a history of SLE and cutaneous lupus treated with hydroxychloroquine 200 mg twice daily and topical corticosteroids. She had started sulfamethoxazole-trimethoprim for a urinary tract infection with a rash appearing 1 day later. She reported burning skin pain with progression to blisters that “sloughed” off. She denied any known history of allergy to sulfa drugs. Prior to evaluation by dermatology, she visited an urgent care facility and was prescribed hydroxyzine and intramuscular corticosteroids. At presentation to dermatology 3 days after taking sulfamethoxazole-trimethoprim, she had annular flaccid bullae and superficial erosions with dusky borders on the right posterior thigh, right side of the chest, left inframammary fold, and right inguinal fold (Figure 1). She had no ocular, oral, or vaginal erosions. A diagnosis of generalized bullous FDE was favored over erythema multiforme or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Shave biopsies from lesions on the right posterior thigh and right inguinal fold demonstrated interface dermatitis with epidermal necrosis, pigment incontinence, and numerous eosinophils. Direct immunofluorescence of the perilesional skin was negative for immunoprotein deposition. These findings were consistent with the clinical impression of generalized bullous FDE. Prior to receiving the histopathology report, the patient was initiated on a regimen of cyclosporine 5 mg/kg/d in the setting of normal renal function and followed until the eruption resolved completely. Cyclosporine was tapered at 2 weeks and discontinued at 3 weeks.
Patient 2—A 32-year-old woman presented for follow-up management of discoid lupus erythematosus. She had a history of systemic and cutaneous lupus, juvenile rheumatoid arthritis, and mixed connective tissue disease managed with prednisone, hydroxychloroquine, azathioprine, and belimumab. Physical examination revealed scarring alopecia with dyspigmentation and active inflammation consistent with uncontrolled cutaneous lupus. However, she also had oval-shaped hyperpigmented patches over the left breast, clavicle, and anterior chest consistent with a generalized FDE (Figure 2). The patient did not recall a history of similar lesions and could not identify a possible trigger. She was counseled on possible culprits and advised to avoid unnecessary medications. She had an unremarkable clinical course; therefore, no further intervention was necessary.
Patient 3—A 33-year-old man presented to the emergency department with a painful rash on the chest and back of 2 days’ duration that began 1 hour after taking naproxen (dosage unknown) for back pain. He had no notable medical history. The patient stated that the rash had slowly worsened and started to develop blisters. He visited an urgent care facility 1 day prior to the current presentation and was started on a 5-day course of prednisone 40 mg daily; the first 2 doses did not help. He denied any mucosal involvement apart from a tender lesion on the penis. He reported a history of an allergic reaction to penicillin. Physical examination revealed extensive dusky violaceous annular plaques with erythematous borders across the anterior and posterior trunk (Figure 3). Multiple flaccid bullae developed within these plaques, involving 15% of the body surface area. He was diagnosed with generalized bullous FDE based on the clinical history and histopathology. He was admitted to the burn intensive care unit and treated with cyclosporine 3 mg/kg/d with subsequent resolution of the eruption.
Comment
Presentation of FDEs—A fixed drug eruption manifests with 1 or more well-demarcated, red or violaceous, annular patches that resolve with postinflammatory hyperpigmentation; it occasionally may manifest with bullae. Initial eruptions may occur up to 2 weeks following medication exposure, but recurrent eruptions usually happen within minutes to hours later. They often are in the same location as prior lesions. A fixed drug eruption can be solitary, scattered, or generalized; a generalized FDE typically demonstrates multiple bilateral lesions that may itch, burn, or cause no symptoms. Patients can experience an FDE at any age, though the median age is reported as 35 to 60 years of age.1 A fixed drug eruption usually occurs after ingestion of oral medications, though there have been a few reports with iodinated contrast.2 Well-known culprits include antibiotics (eg, sulfamethoxazole-trimethoprim, tetracyclines, penicillins/cephalosporins, quinolones, dapsone), nonsteroidal anti-inflammatory drugs, acetaminophen (eg, paracetamol), barbiturates, antimalarials, and anticonvulsants. It also can occur with vaccines or with certain foods (fixed food eruption).3,4 Clinicians may try an oral drug challenge to identify the cause of an FDE, but in patients with a history of a generalized FDE, the risk for developing an increasingly severe reaction with repeated exposure to the medication is too high.5
Histopathology—Patch testing at the site of prior eruption with suspected drug culprits may be useful.6 Histopathology of FDE typically demonstrates vacuolar changes at the dermoepidermal junction with a lichenoid lymphocytic infiltrate. Early lesions often show a predominance of eosinophils. Subepidermal clefting is a feature of the bullous variant. In an active lesion, there are large numbers of CD8+ T lymphocytes expressing natural killer cell–associated molecules.7 The pathologic mechanism is not well understood, though it has been hypothesized that memory CD8+ cells are maintained in specific regions of the epidermis by IL-15 produced in the microenvironment and are activated upon rechallenge.7Considerations in Generalized Bullous FDE—Generalized FDE is defined in the literature as an FDE with involvement of 3 of 6 body areas: head, neck, trunk, upper limbs, lower limbs, and genital area. It may cover more or less than 10% of the body surface area.8-10 Although an isolated FDE frequently is asymptomatic and may not be cause for alarm, recurring drug eruptions increase the risk for development of generalized bullous FDE. Generalized bullous FDE is a rare subset. It is frequently misdiagnosed, and data on its incidence are uncertain.11 Of note, several pathologies causing bullous lesions may be in the differential diagnosis, including bullous pemphigoid; pemphigus vulgaris; bullous SLE; or bullae from cutaneous lupus, staphylococcal scalded skin syndrome, erythema multiforme, or SJS/TEN.12 When matched for body surface area involvement with SJS/TEN, generalized bullous FDE shares nearly identical mortality rates10; therefore, these patients should be treated with the same level of urgency and admitted to a critical care or burn unit, as they are at serious risk for infection and other complications.13
Clinical history and presentation along with histopathologic findings help to narrow down the differential diagnosis. Clinically, generalized bullous FDE does not affect the surrounding skin and manifests sooner after drug exposure (1–24 hours) with less mucosal involvement than SJS/TEN.9 Additionally, SJS/TEN patients frequently have generalized malaise and/or fever, while generalized bullous FDE patients do not. Finally, patients with generalized bullous FDE may report a history of a cutaneous eruption similar in morphology or in the same location.
Histopathologically, generalized bullous FDE may be similar to FDE with the addition of a subepidermal blister. Generalized bullous FDE patients have greater eosinophil infiltration and dermal melanophages than patients with SJS/TEN.9 Cellular infiltrates in generalized bullous FDE include more dermal CD41 cells, such as Foxp31 regulatory T cells; fewer intraepidermal CD561 cells; and fewer intraepidermal cells with granulysin.9 Occasionally, generalized bullous FDE causes full-thickness necrosis. In those cases, generalized bullous FDE cannot reliably be distinguished from other conditions with epidermal necrolysis on histopathology.13
FDE Diagnostics—A cytotoxin produced by
Management—Avoidance of the inciting drug often is sufficient for patients with an FDE, as demonstrated in patient 2 in our case series. Clinicians also should counsel patients on avoidance of potential cross-reacting drugs. Symptomatic treatment for itch or pain is appropriate and may include antihistamines or topical steroids. Nonsteroidal anti-inflammatory drugs may exacerbate or be causative of FDE. For generalized bullous FDE, cyclosporine is favored in the literature15,16 and was used to successfully treat both patients 1 and 3 in our case series. A short course of systemic corticosteroids or intravenous immunoglobulin also may be considered. Mild cases of generalized bullous FDE may be treated with close outpatient follow-up (patient 1), while severe cases require inpatient or even critical care monitoring with aggressive medical management to prevent the progression of skin desquamation (patient 3). Patients with severe oral lesions may require inpatient support for fluid maintenance.
Lupus History—Two patients in our case series had a history of lupus. Lupus itself can cause primary bullous lesions. Similar to FDE, bullous SLE can involve sun-exposed and nonexposed areas of the skin as well as the mucous membranes with a predilection for the lower vermilion lip.17 In bullous SLE, tense subepidermal blisters with a neutrophil-rich infiltrate form due to circulating antibodies to type VII collagen. These blisters have an erythematous or urticated base, most commonly on the face, upper trunk, and proximal extremities.18 In both SLE with skin manifestations and lupus limited to the skin, bullae may form due to extensive vacuolar degeneration. Similar to TEN, they can form rapidly in a widespread distribution.17 However, there is limited mucosal involvement, no clear drug association, and a better prognosis. Bullae caused by lupus will frequently demonstrate deposition of immunoproteins IgG, IgM, IgA, and complement component 3 at the basement membrane zone in perilesional skin on direct immunofluorescence. However, negative direct immunofluorescence does not rule out lupus.12 At the same time, patients with lupus frequently have comorbidities requiring multiple medications; the need for these medications may predispose patients to higher rates of cutaneous drug eruptions.19 To our knowledge, there is no known association between FDE and lupus.
Conclusion
Patients with acute eruptions following the initiation of a new prescription or over-the-counter medication require urgent evaluation. Generalized bullous FDE requires timely diagnosis and intervention. Patients with lupus have an increased risk for cutaneous drug eruptions due to polypharmacy. Further investigation is necessary to determine if there is a pathophysiologic mechanism responsible for the development of FDE in lupus patients.
- Anderson HJ, Lee JB. A review of fixed drug eruption with a special focus on generalized bullous fixed drug eruption. Medicina (Kaunas). 2021;57:925.
- Gavin M, Sharp L, Walker K, et al. Contrast-induced generalized bullous fixed drug eruption resembling Stevens-Johnson syndrome. Proc (Bayl Univ Med Cent). 2019;32:601-602.
- Kabir S, Feit EJ, Heilman ER. Generalized fixed drug eruption following Pfizer-BioNtech COVID-19 vaccination. Clin Case Rep. 2022;10:E6684.
- Choi S, Kim SH, Hwang JH, et al. Rapidly progressing generalized bullous fixed drug eruption after the first dose of COVID-19 messenger RNA vaccination. J Dermatol. 2023;50:1190-1193.
- Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;37:833-838.
- Shiohara T. Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol. 2009;9:316-321.
- Mizukawa Y, Yamazaki Y, Shiohara T. In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Br J Dermatol. 2008;158:1230-1238.
- Lee CH, Chen YC, Cho YT, et al. Fixed-drug eruption: a retrospective study in a single referral center in northern Taiwan. Dermatologica Sinica. 2012;30:11-15.
- Cho YT, Lin JW, Chen YC, et al. Generalized bullous fixed drug eruption is distinct from Stevens-Johnson syndrome/toxic epidermal necrolysis by immunohistopathological features. J Am Acad Dermatol. 2014;70:539-548.
- Lipowicz S, Sekula P, Ingen-Housz-Oro S, et al. Prognosis of generalized bullous fixed drug eruption: comparison with Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 2013;168:726-732.
- Patel S, John AM, Handler MZ, et al. Fixed drug eruptions: an update, emphasizing the potentially lethal generalized bullous fixed drug eruption. Am J Clin Dermatol. 2020;21:393-399.
- Ranario JS, Smith JL. Bullous lesions in a patient with systemic lupus erythematosus. J Clin Aesthet Dermatol. 2014;7:44-49.
- Perron E, Viarnaud A, Marciano L, et al. Clinical and histological features of fixed drug eruption: a single-centre series of 73 cases with comparison between bullous and non-bullous forms. Eur J Dermatol. 2021;31:372-380.
- Chen CB, Kuo KL, Wang CW, et al. Detecting lesional granulysin levels for rapid diagnosis of cytotoxic T lymphocyte-mediated bullous skin disorders. J Allergy Clin Immunol Pract. 2021;9:1327-1337.e3.
- Beniwal R, Gupta LK, Khare AK, et al. Cyclosporine in generalized bullous-fixed drug eruption. Indian J Dermatol. 2018;63:432-433.
- Vargas Mora P, García S, Valenzuela F, et al. Generalized bullous fixed drug eruption successfully treated with cyclosporine. Dermatol Ther. 2020;33:E13492.
- Montagnon CM, Tolkachjov SN, Murrell DF, et al. Subepithelial autoimmune blistering dermatoses: clinical features and diagnosis. J Am Acad Dermatol. 2021;85:1-14.
- Sebaratnam DF, Murrell DF. Bullous systemic lupus erythematosus. Dermatol Clin. 2011;29:649-653.
- Zonzits E, Aberer W, Tappeiner G. Drug eruptions from mesna. After cyclophosphamide treatment of patients with systemic lupus erythematosus and dermatomyositis. Arch Dermatol. 1992;128:80-82.
- Anderson HJ, Lee JB. A review of fixed drug eruption with a special focus on generalized bullous fixed drug eruption. Medicina (Kaunas). 2021;57:925.
- Gavin M, Sharp L, Walker K, et al. Contrast-induced generalized bullous fixed drug eruption resembling Stevens-Johnson syndrome. Proc (Bayl Univ Med Cent). 2019;32:601-602.
- Kabir S, Feit EJ, Heilman ER. Generalized fixed drug eruption following Pfizer-BioNtech COVID-19 vaccination. Clin Case Rep. 2022;10:E6684.
- Choi S, Kim SH, Hwang JH, et al. Rapidly progressing generalized bullous fixed drug eruption after the first dose of COVID-19 messenger RNA vaccination. J Dermatol. 2023;50:1190-1193.
- Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;37:833-838.
- Shiohara T. Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol. 2009;9:316-321.
- Mizukawa Y, Yamazaki Y, Shiohara T. In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Br J Dermatol. 2008;158:1230-1238.
- Lee CH, Chen YC, Cho YT, et al. Fixed-drug eruption: a retrospective study in a single referral center in northern Taiwan. Dermatologica Sinica. 2012;30:11-15.
- Cho YT, Lin JW, Chen YC, et al. Generalized bullous fixed drug eruption is distinct from Stevens-Johnson syndrome/toxic epidermal necrolysis by immunohistopathological features. J Am Acad Dermatol. 2014;70:539-548.
- Lipowicz S, Sekula P, Ingen-Housz-Oro S, et al. Prognosis of generalized bullous fixed drug eruption: comparison with Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 2013;168:726-732.
- Patel S, John AM, Handler MZ, et al. Fixed drug eruptions: an update, emphasizing the potentially lethal generalized bullous fixed drug eruption. Am J Clin Dermatol. 2020;21:393-399.
- Ranario JS, Smith JL. Bullous lesions in a patient with systemic lupus erythematosus. J Clin Aesthet Dermatol. 2014;7:44-49.
- Perron E, Viarnaud A, Marciano L, et al. Clinical and histological features of fixed drug eruption: a single-centre series of 73 cases with comparison between bullous and non-bullous forms. Eur J Dermatol. 2021;31:372-380.
- Chen CB, Kuo KL, Wang CW, et al. Detecting lesional granulysin levels for rapid diagnosis of cytotoxic T lymphocyte-mediated bullous skin disorders. J Allergy Clin Immunol Pract. 2021;9:1327-1337.e3.
- Beniwal R, Gupta LK, Khare AK, et al. Cyclosporine in generalized bullous-fixed drug eruption. Indian J Dermatol. 2018;63:432-433.
- Vargas Mora P, García S, Valenzuela F, et al. Generalized bullous fixed drug eruption successfully treated with cyclosporine. Dermatol Ther. 2020;33:E13492.
- Montagnon CM, Tolkachjov SN, Murrell DF, et al. Subepithelial autoimmune blistering dermatoses: clinical features and diagnosis. J Am Acad Dermatol. 2021;85:1-14.
- Sebaratnam DF, Murrell DF. Bullous systemic lupus erythematosus. Dermatol Clin. 2011;29:649-653.
- Zonzits E, Aberer W, Tappeiner G. Drug eruptions from mesna. After cyclophosphamide treatment of patients with systemic lupus erythematosus and dermatomyositis. Arch Dermatol. 1992;128:80-82.
Practice Points
- Although localized fixed drug eruption (FDE) is a relatively benign diagnosis, generalized bullous FDE requires urgent management and may necessitate intensive burn care.
- Patients with lupus are at increased risk for drug eruptions due to polypharmacy, and there is a wide differential for bullous eruptions in these patients.
Two New Studies on Benzoyl Peroxide Provide Reassuring Data on Safety
Two .
Earlier this year, controversy erupted after an independent lab Valisure petitioned the US Food and Drug Administration (FDA) to recall acne products with BP because it found extremely high levels of the carcinogen benzene. In the research, the lab directors contended that the products can form over 800 times the “conditionally restricted” FDA concentration limit of 2 parts per million (ppm) of benzene, with both prescription and over-the-counter (OTC) products affected. The issue, according to the lab’s report, is one of degradation, not contamination; BP can decompose into benzene. Exposures to benzene have been linked with a higher risk for leukemia and other blood cancers.
(“Conditionally restricted” means that the maximum of 2 ppm only applies to a drug product in which the use of benzene is unavoidable in order to produce a drug product with a significant therapeutic advance, according to FDA guidance.)
Critics of the report questioned the method used to test the products, calling for more “real-world” use data, and said the temperature used may not be what is expected with everyday use.
Now, both new studies are reassuring about the safety of the products, John Barbieri, MD, MBA, assistant professor of dermatology at Harvard Medical School and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, said in a telephone interview. He was a coauthor of both studies. A leading dermatologist not involved in the new research reviewed the findings and agreed.
One study using data from the National Health and Nutrition Examination Survey compared blood levels of benzene between 14 people who had used BP products and 65 people without a history of BP product use, finding no difference between the groups .
The other, much larger study analyzed electronic health records of more than 27,000 patients with acne using BP products, comparing them with more than 27,000 controls who did not use the products. The patients were followed for 10 years after the use of BP products began, and no increased risk for cancer, either blood cancers or solid tumors, was found.
The studies were recently published in the Journal of the American Academy of Dermatology.
“Both studies are well done,” said Henry W. Lim, MD, former chair of the Department of Dermatology and senior vice president for academic affairs at Henry Ford Health, Detroit. Dr. Lim, a former president of the American Academy of Dermatology, reviewed the results of both studies.
“These studies indicate that [a] report of detection of benzene in [BP] products exposed to high temperature does not have any relevant clinical significance, both in terms of blood levels and in terms of internal cancer,” Dr. Lim said. “This is consistent with the clinical experience of practicing dermatologists; no internal side effects have been observed in patients using [BP products].”
Further Details
Under high temperatures, or over a long period, BP can decompose to benzene, a colorless, flammable liquid with a sweet odor. Benzene is formed from natural processes such as forest fires and volcanoes, according to the American Cancer Society, and is found in the air, cigarette smoke, some foods (at low levels), and contaminated drinking water. It’s one of the 20 widely used chemicals involved in making plastics, resins, detergents, and pesticides, among other products.
In the study evaluating blood levels, the researchers matched 14 people who used BP products currently with 65 controls who did not. Five (36%) of those using the products had detectable blood levels; 21 (32%) of those who did not use them did. There was no association between BP exposure and detectable blood benzene levels (odds ratio, 1.12; P = .80).
In the larger study, the researchers used the TriNetX US Collaborative Network database, comparing more than 27,000 patients treated with BP products for acne with more than 27,000 patients aged 12-40 years who had a diagnosis of nevus or seborrheic keratosis with no exposure to prescribed BP or any diagnosis of acne, hidradenitis suppurativa, or rosacea. The researchers looked at the database over the subsequent 10 years to determine the risk for either blood cancers or internal malignancies.
Compared with patients diagnosed with nevus or seborrheic keratosis, those with acne treated with BP had no significant difference in the risk for lymphoma (hazard ratio [HR], 1.00), leukemia (HR, 0.91), any lymphoma or leukemia (HR, 1.04), and internal malignancies (HR, 0.93).
The findings suggest no increased risk for malignancy, the researchers said, although they acknowledged study limitations, such as possible misclassification of BP exposure due to OTC availability and other issues.
Value of BP Treatments
BP is the “go-to” acne treatment, as Dr. Barbieri pointed out. “It’s probably the number one treatment for acne,” and there’s no substitute for it and it’s one of the most effective topical acne treatments, he noted.
Despite the reassuring findings, Dr. Barbieri repeated advice he gave soon after the Valisure report was released. Use common sense and don’t store BP-containing products in hot cars or other hot environments. In warmer climates, refrigeration could be considered, he said. Discard old products. Manufacturers should use cold-chain storage from the manufacturing site to retail or pharmacy sale sites, he added.
FDA and Citizen Petition Status
Asked about the status of the petition from Valisure, an FDA spokesperson said: “The FDA does not comment on the status of pending petitions.”
Dr. Barbieri and Dr. Lim had no relevant disclosures. There were no funding sources for either of the two studies.
A version of this article first appeared on Medscape.com.
Two .
Earlier this year, controversy erupted after an independent lab Valisure petitioned the US Food and Drug Administration (FDA) to recall acne products with BP because it found extremely high levels of the carcinogen benzene. In the research, the lab directors contended that the products can form over 800 times the “conditionally restricted” FDA concentration limit of 2 parts per million (ppm) of benzene, with both prescription and over-the-counter (OTC) products affected. The issue, according to the lab’s report, is one of degradation, not contamination; BP can decompose into benzene. Exposures to benzene have been linked with a higher risk for leukemia and other blood cancers.
(“Conditionally restricted” means that the maximum of 2 ppm only applies to a drug product in which the use of benzene is unavoidable in order to produce a drug product with a significant therapeutic advance, according to FDA guidance.)
Critics of the report questioned the method used to test the products, calling for more “real-world” use data, and said the temperature used may not be what is expected with everyday use.
Now, both new studies are reassuring about the safety of the products, John Barbieri, MD, MBA, assistant professor of dermatology at Harvard Medical School and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, said in a telephone interview. He was a coauthor of both studies. A leading dermatologist not involved in the new research reviewed the findings and agreed.
One study using data from the National Health and Nutrition Examination Survey compared blood levels of benzene between 14 people who had used BP products and 65 people without a history of BP product use, finding no difference between the groups .
The other, much larger study analyzed electronic health records of more than 27,000 patients with acne using BP products, comparing them with more than 27,000 controls who did not use the products. The patients were followed for 10 years after the use of BP products began, and no increased risk for cancer, either blood cancers or solid tumors, was found.
The studies were recently published in the Journal of the American Academy of Dermatology.
“Both studies are well done,” said Henry W. Lim, MD, former chair of the Department of Dermatology and senior vice president for academic affairs at Henry Ford Health, Detroit. Dr. Lim, a former president of the American Academy of Dermatology, reviewed the results of both studies.
“These studies indicate that [a] report of detection of benzene in [BP] products exposed to high temperature does not have any relevant clinical significance, both in terms of blood levels and in terms of internal cancer,” Dr. Lim said. “This is consistent with the clinical experience of practicing dermatologists; no internal side effects have been observed in patients using [BP products].”
Further Details
Under high temperatures, or over a long period, BP can decompose to benzene, a colorless, flammable liquid with a sweet odor. Benzene is formed from natural processes such as forest fires and volcanoes, according to the American Cancer Society, and is found in the air, cigarette smoke, some foods (at low levels), and contaminated drinking water. It’s one of the 20 widely used chemicals involved in making plastics, resins, detergents, and pesticides, among other products.
In the study evaluating blood levels, the researchers matched 14 people who used BP products currently with 65 controls who did not. Five (36%) of those using the products had detectable blood levels; 21 (32%) of those who did not use them did. There was no association between BP exposure and detectable blood benzene levels (odds ratio, 1.12; P = .80).
In the larger study, the researchers used the TriNetX US Collaborative Network database, comparing more than 27,000 patients treated with BP products for acne with more than 27,000 patients aged 12-40 years who had a diagnosis of nevus or seborrheic keratosis with no exposure to prescribed BP or any diagnosis of acne, hidradenitis suppurativa, or rosacea. The researchers looked at the database over the subsequent 10 years to determine the risk for either blood cancers or internal malignancies.
Compared with patients diagnosed with nevus or seborrheic keratosis, those with acne treated with BP had no significant difference in the risk for lymphoma (hazard ratio [HR], 1.00), leukemia (HR, 0.91), any lymphoma or leukemia (HR, 1.04), and internal malignancies (HR, 0.93).
The findings suggest no increased risk for malignancy, the researchers said, although they acknowledged study limitations, such as possible misclassification of BP exposure due to OTC availability and other issues.
Value of BP Treatments
BP is the “go-to” acne treatment, as Dr. Barbieri pointed out. “It’s probably the number one treatment for acne,” and there’s no substitute for it and it’s one of the most effective topical acne treatments, he noted.
Despite the reassuring findings, Dr. Barbieri repeated advice he gave soon after the Valisure report was released. Use common sense and don’t store BP-containing products in hot cars or other hot environments. In warmer climates, refrigeration could be considered, he said. Discard old products. Manufacturers should use cold-chain storage from the manufacturing site to retail or pharmacy sale sites, he added.
FDA and Citizen Petition Status
Asked about the status of the petition from Valisure, an FDA spokesperson said: “The FDA does not comment on the status of pending petitions.”
Dr. Barbieri and Dr. Lim had no relevant disclosures. There were no funding sources for either of the two studies.
A version of this article first appeared on Medscape.com.
Two .
Earlier this year, controversy erupted after an independent lab Valisure petitioned the US Food and Drug Administration (FDA) to recall acne products with BP because it found extremely high levels of the carcinogen benzene. In the research, the lab directors contended that the products can form over 800 times the “conditionally restricted” FDA concentration limit of 2 parts per million (ppm) of benzene, with both prescription and over-the-counter (OTC) products affected. The issue, according to the lab’s report, is one of degradation, not contamination; BP can decompose into benzene. Exposures to benzene have been linked with a higher risk for leukemia and other blood cancers.
(“Conditionally restricted” means that the maximum of 2 ppm only applies to a drug product in which the use of benzene is unavoidable in order to produce a drug product with a significant therapeutic advance, according to FDA guidance.)
Critics of the report questioned the method used to test the products, calling for more “real-world” use data, and said the temperature used may not be what is expected with everyday use.
Now, both new studies are reassuring about the safety of the products, John Barbieri, MD, MBA, assistant professor of dermatology at Harvard Medical School and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, said in a telephone interview. He was a coauthor of both studies. A leading dermatologist not involved in the new research reviewed the findings and agreed.
One study using data from the National Health and Nutrition Examination Survey compared blood levels of benzene between 14 people who had used BP products and 65 people without a history of BP product use, finding no difference between the groups .
The other, much larger study analyzed electronic health records of more than 27,000 patients with acne using BP products, comparing them with more than 27,000 controls who did not use the products. The patients were followed for 10 years after the use of BP products began, and no increased risk for cancer, either blood cancers or solid tumors, was found.
The studies were recently published in the Journal of the American Academy of Dermatology.
“Both studies are well done,” said Henry W. Lim, MD, former chair of the Department of Dermatology and senior vice president for academic affairs at Henry Ford Health, Detroit. Dr. Lim, a former president of the American Academy of Dermatology, reviewed the results of both studies.
“These studies indicate that [a] report of detection of benzene in [BP] products exposed to high temperature does not have any relevant clinical significance, both in terms of blood levels and in terms of internal cancer,” Dr. Lim said. “This is consistent with the clinical experience of practicing dermatologists; no internal side effects have been observed in patients using [BP products].”
Further Details
Under high temperatures, or over a long period, BP can decompose to benzene, a colorless, flammable liquid with a sweet odor. Benzene is formed from natural processes such as forest fires and volcanoes, according to the American Cancer Society, and is found in the air, cigarette smoke, some foods (at low levels), and contaminated drinking water. It’s one of the 20 widely used chemicals involved in making plastics, resins, detergents, and pesticides, among other products.
In the study evaluating blood levels, the researchers matched 14 people who used BP products currently with 65 controls who did not. Five (36%) of those using the products had detectable blood levels; 21 (32%) of those who did not use them did. There was no association between BP exposure and detectable blood benzene levels (odds ratio, 1.12; P = .80).
In the larger study, the researchers used the TriNetX US Collaborative Network database, comparing more than 27,000 patients treated with BP products for acne with more than 27,000 patients aged 12-40 years who had a diagnosis of nevus or seborrheic keratosis with no exposure to prescribed BP or any diagnosis of acne, hidradenitis suppurativa, or rosacea. The researchers looked at the database over the subsequent 10 years to determine the risk for either blood cancers or internal malignancies.
Compared with patients diagnosed with nevus or seborrheic keratosis, those with acne treated with BP had no significant difference in the risk for lymphoma (hazard ratio [HR], 1.00), leukemia (HR, 0.91), any lymphoma or leukemia (HR, 1.04), and internal malignancies (HR, 0.93).
The findings suggest no increased risk for malignancy, the researchers said, although they acknowledged study limitations, such as possible misclassification of BP exposure due to OTC availability and other issues.
Value of BP Treatments
BP is the “go-to” acne treatment, as Dr. Barbieri pointed out. “It’s probably the number one treatment for acne,” and there’s no substitute for it and it’s one of the most effective topical acne treatments, he noted.
Despite the reassuring findings, Dr. Barbieri repeated advice he gave soon after the Valisure report was released. Use common sense and don’t store BP-containing products in hot cars or other hot environments. In warmer climates, refrigeration could be considered, he said. Discard old products. Manufacturers should use cold-chain storage from the manufacturing site to retail or pharmacy sale sites, he added.
FDA and Citizen Petition Status
Asked about the status of the petition from Valisure, an FDA spokesperson said: “The FDA does not comment on the status of pending petitions.”
Dr. Barbieri and Dr. Lim had no relevant disclosures. There were no funding sources for either of the two studies.
A version of this article first appeared on Medscape.com.
Greater Transparency of Oncologists’ Pharma Relationships Needed
The findings reflect limited awareness in low-income countries about what scenarios constitute a conflict of interest, first author, Khalid El Bairi, MD, said during an interview. “There is a lack of training in ethics and integrity in medical schools [in countries in Africa], so people are not informed about conflicts of interest,” continued Dr. El Bairi, who presented the new research at the annual meeting of the American Society of Clinical Oncology. “There is also a lack of policies in universities and hospitals to guide clinicians about conflict of interest reporting.”
Overall, 58.5% of survey participants categorized honoraria as a conflict of interest that required disclosure, while 50% said the same of gifts from pharmaceutical representatives, and 44.5% identified travel grants for attending conferences as conflicts of interests. The report was published in JCO Global Oncology. Less often considered conflicts of interest were personal and institutional research funding, trips to conferences, consulting or advisory roles, food and beverages, expert testimony, and sample drugs provided by the pharmaceutical industry.
Just 24% of participants indicated that all of the listed items were deemed conflicts of interest. The survey — called Oncology Transparency Under Scrutiny and Tracking, or ONCOTRUST-1 — considered the perceptions of 200 oncologists, about 70% of whom practice in low- and middle-income countries.
What’s more, 37.5% of respondents identified fear of losing financial support as a reason not to report a conflict of interest. Still, 75% indicated that industry-sponsored speaking does not affect treatment decisions, and 60% said conflicts of interest do not impair objective appraisal of clinical trials.
Dr. El Bairi, a research associate in the department of medical oncology at Mohammed VI University Hospital, Oujda, Morocco, and his colleagues undertook the study in part because of an editorial published in The Lancet Oncology last year. First author Fidel Rubagumya, MD, a consultant oncologist and director of research at Rwanda Military Hospital, Kigali, and colleagues called for more research on the ties between oncologists and industry in Africa. The ONCOTRUST-1 findings set the stage for a planned follow-up study, which aims to compare views surrounding conflicts of interests between oncologists in different economic settings.
Open Payments Houses US Physicians’ Conflicts of Interest
To be sure, many authors of research published in major US journals are based outside of the United States. According to JAMA Network Open, 69% of submissions to the journal are from international authors. However, Dr. El Bairi also raised other potential signs of industry influence that he said need global discussion, such as the role of pharmaceutical companies in presentations of clinical trial findings at large cancer societies’ conferences, a shift toward progression-free survival as the endpoint in clinical cancer trials, and the rise of third-party writing assistance.
“There are two sides of the story,” Dr. El Bairi said. “The good side is that unfortunately, sometimes [industry money is] the only way for African oncologists to go abroad for training, to conferences for their continuous medical education. The bad is now we may harm patients, we might harm science by having conflicts of interest not reported.”
Unlike other countries, the United States has plentiful data on the scale of physicians’ financial conflicts of interest in the form of the Open Payments platform. Championed by Sen. Chuck Grassley (R-Iowa), the federal repository of payments to doctors and teaching hospitals by drug and medical device companies was established as part of the Affordable Care Act (ACA).
The health care reform law, which passed in 2010, requires pharmaceutical companies and medical device makers to report this information.
From 2013 to 2021, the pharmaceutical and medical device industry paid physicians $12.1 billion, according to a research letter published in JAMA in March of 2024 that reviewed Open Payments data.
Ranked by specialty, hematologists and oncologists received the fourth-largest amount of money in aggregate, the study shows. Their total of $825.8 million trailed only physicians in orthopedics ($1.36 billion), neurology and psychiatry ($1.32 billion) and cardiology ($1.29 billion). What’s more, this specialty had the biggest share of physicians taking industry money, with 74.2% of hematologists and oncologists receiving payments.
The payments from industry include fees for consulting services and speaking, as well as food and beverages, travel and lodging, education, gifts, grants, and honoraria.
Joseph S. Ross, MD, MHS, one of the JAMA study’s coauthors, said in an interview that the continued prevalence of such funding runs counter to the expectation behind the measure, which was that transparency would lead to physicians’ becoming less likely to accept a payment.
“We as a profession need to take a cold hard look in the mirror,” he said, referring to physicians in general.
Dr. Ross, professor of medicine at Yale University School of Medicine, New Haven, Connecticut, said he hopes that the profession will self-police, and that patients will make a bigger deal of the issue. Still, he acknowledged that “the vast majority” of patient advocacy groups, too, are funded by the pharmaceutical industry.
Exposing Industry Payments May Have Perverse Effect
A growing body of research explores the effect that physicians’ financial relationships with pharmaceutical companies can have on their prescribing practices. Indeed, oncologists taking industry payments seem to be more likely to prescribe nonrecommended and low-value drugs in some clinical settings, according to a study published in The BMJ last year.
That study’s first author, Aaron P. Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center, New York City, suggested in an interview that exposing industry payments to the sunlight may have had a perverse effect on physicians.
“There’s this idea of having license to do something,” Dr. Mitchell said, speaking broadly about human psychology rather than drawing on empirical data. “You might feel a little less bad about then prescribing more of that company’s drug, because the disclosure has already been done.”
The influence of pharmaceutical industry money on oncologists goes beyond what’s prescribed to which treatments get studied, approved, and recommended by guidelines, Dr. Mitchell said. He was also first author of a 2016 paper published in JAMA Oncology that found 86% of authors of the National Comprehensive Cancer Network guidelines had at least one conflict of interest reported on Open Systems in 2014.
Meanwhile, the fact that physicians’ payments from industry are a matter of public record on Open Systems has not guaranteed that doctors will disclose their conflicts of interest in other forums. A study published in JAMA earlier this year, for which Dr. Mitchell served as first author, found that almost one in three physicians endorsing drugs and devices on the social media platform X failed to disclose that the manufacturer paid them.
The lack of disclosure seems to extend beyond social media. A 2018 study published in JAMA Oncology found that 32% of oncologist authors of clinical drug trials for drugs approved over a 20-month period from 2016 to 2017 did not fully disclose payments from the trial sponsor when checked against the Open Payments database.
A lion’s share of industry payments within oncology appears to be going to a small group of high-profile physicians, suggested a 2022 study published in JCO Oncology Practice. It found that just 1% of all US oncologists accounted for 37% of industry payments, with each receiving more than $100,000 a year.
Experts: Professional Societies Should Further Limit Industry Payments
While partnerships between drug companies and physicians are necessary and have often been positive, more than disclosure is needed to minimize the risk of patient harm, according to an editorial published in March in JCO Oncology Practice. In it, Nina Niu Sanford, MD, a radiation oncologist UT Southwestern Medical Center, Dallas, and Bishal Gyawali, MD, PhD, a medical oncologist at Queen’s University, Kingston, Ontario, Canada, argue that following a specific blueprint could help mitigate financial conflicts of interest.
For starters, Dr. Sanford and Dr. Gyawali contend in the editorial that the maximum general payment NCCN members are allowed to receive from industry should be $0, compared with a current bar of $20,000 from a single entity or $50,000 from all external entities combined. They also urge professional societies to follow the current policy of the American Society of Clinical Oncology and ban members serving in their leadership from receiving any general payments from the industry.
The authors further suggest that investigators of clinical trials should be barred from holding stock for the drug or product while it is under study and that editorialists should not have conflicts of interest with the company whose drug or product they are discussing.
Pharmaceutical money can harm patients in ways that are not always obvious, Dr. Gyawali said in an interview.
“It can dominate the conversation by removing critical viewpoints from these top people about certain drugs,” he said. “It’s not always about saying good things about the drug.”
For instance, he suggested, a doctor receiving payments from Pfizer might openly criticize perceived flaws in drugs from other companies but refrain from weighing in negatively on a Pfizer drug.
From 2016 to 2018, industry made general payments to more than 52,000 physicians for 137 unique cancer drugs, according to a separate 2021 study published in the Journal of Cancer Policy, for which Dr. Gyawali served as one of the coauthors.
The results suggest that pharmaceutical money affects the entire cancer system, not relatively few oncology leaders. The amounts and dollar values grew each year covered by the study, to nearly 466,000 payments totaling $98.5 million in 2018.
Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, Washington, DC, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices, has called for a ban on industry gifts to physicians.
When a publication asks physicians to disclose relevant conflicts of interest, physicians may choose not to disclose, because they don’t feel that their conflicts are relevant, Dr. Fugh-Berman said. Drug and device makers have also grown sophisticated about how they work with physicians, she suggested. “It’s illegal to market a drug before it comes on the market, but it’s not illegal to market the disease,” said Dr. Fugh-Berman, noting that drugmakers often work on long timelines.
“The doctor is going around saying we don’t have good therapies. They’re not pushing a drug. And so they feel totally fine about it.”
Anecdotally, Dr. Fugh-Berman noted that, if anything, speaking fees and similar payments only improve doctors’ reputations. She said that’s especially true if the physicians are paid by multiple companies, on the supposed theory that their conflicts of interest cancel each other out.
“I’m not defending this,” added Dr. Fugh-Berman, observing that, at the end of the day, such conflicts may go against the interests of patients.
“Sometimes the best drugs are older, generic, cheap drugs, and if oncologists or other specialists are only choosing among the most promoted drugs, they’re not necessarily choosing the best drugs.”
Beyond any prestige, doctors have other possible nonfinancial incentives for receiving industry payments. “It’s the relationships,” Dr. Fugh-Berman said. “Companies are very good at offering friendship.”
Dr. El Bairi reported NCODA leadership and honoraria along with expert testimony through techspert.io. Dr. Ross reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of or the review of the manuscript he authored and discussed in this article. Dr. Ross also reported receiving grants from the Food and Drug Administration, Johnson & Johnson, the Medical Device Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Mitchell reported no relevant financial relationships. Dr. Gyawali reported a consulting or advisory role with Vivio Health. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.
The findings reflect limited awareness in low-income countries about what scenarios constitute a conflict of interest, first author, Khalid El Bairi, MD, said during an interview. “There is a lack of training in ethics and integrity in medical schools [in countries in Africa], so people are not informed about conflicts of interest,” continued Dr. El Bairi, who presented the new research at the annual meeting of the American Society of Clinical Oncology. “There is also a lack of policies in universities and hospitals to guide clinicians about conflict of interest reporting.”
Overall, 58.5% of survey participants categorized honoraria as a conflict of interest that required disclosure, while 50% said the same of gifts from pharmaceutical representatives, and 44.5% identified travel grants for attending conferences as conflicts of interests. The report was published in JCO Global Oncology. Less often considered conflicts of interest were personal and institutional research funding, trips to conferences, consulting or advisory roles, food and beverages, expert testimony, and sample drugs provided by the pharmaceutical industry.
Just 24% of participants indicated that all of the listed items were deemed conflicts of interest. The survey — called Oncology Transparency Under Scrutiny and Tracking, or ONCOTRUST-1 — considered the perceptions of 200 oncologists, about 70% of whom practice in low- and middle-income countries.
What’s more, 37.5% of respondents identified fear of losing financial support as a reason not to report a conflict of interest. Still, 75% indicated that industry-sponsored speaking does not affect treatment decisions, and 60% said conflicts of interest do not impair objective appraisal of clinical trials.
Dr. El Bairi, a research associate in the department of medical oncology at Mohammed VI University Hospital, Oujda, Morocco, and his colleagues undertook the study in part because of an editorial published in The Lancet Oncology last year. First author Fidel Rubagumya, MD, a consultant oncologist and director of research at Rwanda Military Hospital, Kigali, and colleagues called for more research on the ties between oncologists and industry in Africa. The ONCOTRUST-1 findings set the stage for a planned follow-up study, which aims to compare views surrounding conflicts of interests between oncologists in different economic settings.
Open Payments Houses US Physicians’ Conflicts of Interest
To be sure, many authors of research published in major US journals are based outside of the United States. According to JAMA Network Open, 69% of submissions to the journal are from international authors. However, Dr. El Bairi also raised other potential signs of industry influence that he said need global discussion, such as the role of pharmaceutical companies in presentations of clinical trial findings at large cancer societies’ conferences, a shift toward progression-free survival as the endpoint in clinical cancer trials, and the rise of third-party writing assistance.
“There are two sides of the story,” Dr. El Bairi said. “The good side is that unfortunately, sometimes [industry money is] the only way for African oncologists to go abroad for training, to conferences for their continuous medical education. The bad is now we may harm patients, we might harm science by having conflicts of interest not reported.”
Unlike other countries, the United States has plentiful data on the scale of physicians’ financial conflicts of interest in the form of the Open Payments platform. Championed by Sen. Chuck Grassley (R-Iowa), the federal repository of payments to doctors and teaching hospitals by drug and medical device companies was established as part of the Affordable Care Act (ACA).
The health care reform law, which passed in 2010, requires pharmaceutical companies and medical device makers to report this information.
From 2013 to 2021, the pharmaceutical and medical device industry paid physicians $12.1 billion, according to a research letter published in JAMA in March of 2024 that reviewed Open Payments data.
Ranked by specialty, hematologists and oncologists received the fourth-largest amount of money in aggregate, the study shows. Their total of $825.8 million trailed only physicians in orthopedics ($1.36 billion), neurology and psychiatry ($1.32 billion) and cardiology ($1.29 billion). What’s more, this specialty had the biggest share of physicians taking industry money, with 74.2% of hematologists and oncologists receiving payments.
The payments from industry include fees for consulting services and speaking, as well as food and beverages, travel and lodging, education, gifts, grants, and honoraria.
Joseph S. Ross, MD, MHS, one of the JAMA study’s coauthors, said in an interview that the continued prevalence of such funding runs counter to the expectation behind the measure, which was that transparency would lead to physicians’ becoming less likely to accept a payment.
“We as a profession need to take a cold hard look in the mirror,” he said, referring to physicians in general.
Dr. Ross, professor of medicine at Yale University School of Medicine, New Haven, Connecticut, said he hopes that the profession will self-police, and that patients will make a bigger deal of the issue. Still, he acknowledged that “the vast majority” of patient advocacy groups, too, are funded by the pharmaceutical industry.
Exposing Industry Payments May Have Perverse Effect
A growing body of research explores the effect that physicians’ financial relationships with pharmaceutical companies can have on their prescribing practices. Indeed, oncologists taking industry payments seem to be more likely to prescribe nonrecommended and low-value drugs in some clinical settings, according to a study published in The BMJ last year.
That study’s first author, Aaron P. Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center, New York City, suggested in an interview that exposing industry payments to the sunlight may have had a perverse effect on physicians.
“There’s this idea of having license to do something,” Dr. Mitchell said, speaking broadly about human psychology rather than drawing on empirical data. “You might feel a little less bad about then prescribing more of that company’s drug, because the disclosure has already been done.”
The influence of pharmaceutical industry money on oncologists goes beyond what’s prescribed to which treatments get studied, approved, and recommended by guidelines, Dr. Mitchell said. He was also first author of a 2016 paper published in JAMA Oncology that found 86% of authors of the National Comprehensive Cancer Network guidelines had at least one conflict of interest reported on Open Systems in 2014.
Meanwhile, the fact that physicians’ payments from industry are a matter of public record on Open Systems has not guaranteed that doctors will disclose their conflicts of interest in other forums. A study published in JAMA earlier this year, for which Dr. Mitchell served as first author, found that almost one in three physicians endorsing drugs and devices on the social media platform X failed to disclose that the manufacturer paid them.
The lack of disclosure seems to extend beyond social media. A 2018 study published in JAMA Oncology found that 32% of oncologist authors of clinical drug trials for drugs approved over a 20-month period from 2016 to 2017 did not fully disclose payments from the trial sponsor when checked against the Open Payments database.
A lion’s share of industry payments within oncology appears to be going to a small group of high-profile physicians, suggested a 2022 study published in JCO Oncology Practice. It found that just 1% of all US oncologists accounted for 37% of industry payments, with each receiving more than $100,000 a year.
Experts: Professional Societies Should Further Limit Industry Payments
While partnerships between drug companies and physicians are necessary and have often been positive, more than disclosure is needed to minimize the risk of patient harm, according to an editorial published in March in JCO Oncology Practice. In it, Nina Niu Sanford, MD, a radiation oncologist UT Southwestern Medical Center, Dallas, and Bishal Gyawali, MD, PhD, a medical oncologist at Queen’s University, Kingston, Ontario, Canada, argue that following a specific blueprint could help mitigate financial conflicts of interest.
For starters, Dr. Sanford and Dr. Gyawali contend in the editorial that the maximum general payment NCCN members are allowed to receive from industry should be $0, compared with a current bar of $20,000 from a single entity or $50,000 from all external entities combined. They also urge professional societies to follow the current policy of the American Society of Clinical Oncology and ban members serving in their leadership from receiving any general payments from the industry.
The authors further suggest that investigators of clinical trials should be barred from holding stock for the drug or product while it is under study and that editorialists should not have conflicts of interest with the company whose drug or product they are discussing.
Pharmaceutical money can harm patients in ways that are not always obvious, Dr. Gyawali said in an interview.
“It can dominate the conversation by removing critical viewpoints from these top people about certain drugs,” he said. “It’s not always about saying good things about the drug.”
For instance, he suggested, a doctor receiving payments from Pfizer might openly criticize perceived flaws in drugs from other companies but refrain from weighing in negatively on a Pfizer drug.
From 2016 to 2018, industry made general payments to more than 52,000 physicians for 137 unique cancer drugs, according to a separate 2021 study published in the Journal of Cancer Policy, for which Dr. Gyawali served as one of the coauthors.
The results suggest that pharmaceutical money affects the entire cancer system, not relatively few oncology leaders. The amounts and dollar values grew each year covered by the study, to nearly 466,000 payments totaling $98.5 million in 2018.
Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, Washington, DC, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices, has called for a ban on industry gifts to physicians.
When a publication asks physicians to disclose relevant conflicts of interest, physicians may choose not to disclose, because they don’t feel that their conflicts are relevant, Dr. Fugh-Berman said. Drug and device makers have also grown sophisticated about how they work with physicians, she suggested. “It’s illegal to market a drug before it comes on the market, but it’s not illegal to market the disease,” said Dr. Fugh-Berman, noting that drugmakers often work on long timelines.
“The doctor is going around saying we don’t have good therapies. They’re not pushing a drug. And so they feel totally fine about it.”
Anecdotally, Dr. Fugh-Berman noted that, if anything, speaking fees and similar payments only improve doctors’ reputations. She said that’s especially true if the physicians are paid by multiple companies, on the supposed theory that their conflicts of interest cancel each other out.
“I’m not defending this,” added Dr. Fugh-Berman, observing that, at the end of the day, such conflicts may go against the interests of patients.
“Sometimes the best drugs are older, generic, cheap drugs, and if oncologists or other specialists are only choosing among the most promoted drugs, they’re not necessarily choosing the best drugs.”
Beyond any prestige, doctors have other possible nonfinancial incentives for receiving industry payments. “It’s the relationships,” Dr. Fugh-Berman said. “Companies are very good at offering friendship.”
Dr. El Bairi reported NCODA leadership and honoraria along with expert testimony through techspert.io. Dr. Ross reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of or the review of the manuscript he authored and discussed in this article. Dr. Ross also reported receiving grants from the Food and Drug Administration, Johnson & Johnson, the Medical Device Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Mitchell reported no relevant financial relationships. Dr. Gyawali reported a consulting or advisory role with Vivio Health. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.
The findings reflect limited awareness in low-income countries about what scenarios constitute a conflict of interest, first author, Khalid El Bairi, MD, said during an interview. “There is a lack of training in ethics and integrity in medical schools [in countries in Africa], so people are not informed about conflicts of interest,” continued Dr. El Bairi, who presented the new research at the annual meeting of the American Society of Clinical Oncology. “There is also a lack of policies in universities and hospitals to guide clinicians about conflict of interest reporting.”
Overall, 58.5% of survey participants categorized honoraria as a conflict of interest that required disclosure, while 50% said the same of gifts from pharmaceutical representatives, and 44.5% identified travel grants for attending conferences as conflicts of interests. The report was published in JCO Global Oncology. Less often considered conflicts of interest were personal and institutional research funding, trips to conferences, consulting or advisory roles, food and beverages, expert testimony, and sample drugs provided by the pharmaceutical industry.
Just 24% of participants indicated that all of the listed items were deemed conflicts of interest. The survey — called Oncology Transparency Under Scrutiny and Tracking, or ONCOTRUST-1 — considered the perceptions of 200 oncologists, about 70% of whom practice in low- and middle-income countries.
What’s more, 37.5% of respondents identified fear of losing financial support as a reason not to report a conflict of interest. Still, 75% indicated that industry-sponsored speaking does not affect treatment decisions, and 60% said conflicts of interest do not impair objective appraisal of clinical trials.
Dr. El Bairi, a research associate in the department of medical oncology at Mohammed VI University Hospital, Oujda, Morocco, and his colleagues undertook the study in part because of an editorial published in The Lancet Oncology last year. First author Fidel Rubagumya, MD, a consultant oncologist and director of research at Rwanda Military Hospital, Kigali, and colleagues called for more research on the ties between oncologists and industry in Africa. The ONCOTRUST-1 findings set the stage for a planned follow-up study, which aims to compare views surrounding conflicts of interests between oncologists in different economic settings.
Open Payments Houses US Physicians’ Conflicts of Interest
To be sure, many authors of research published in major US journals are based outside of the United States. According to JAMA Network Open, 69% of submissions to the journal are from international authors. However, Dr. El Bairi also raised other potential signs of industry influence that he said need global discussion, such as the role of pharmaceutical companies in presentations of clinical trial findings at large cancer societies’ conferences, a shift toward progression-free survival as the endpoint in clinical cancer trials, and the rise of third-party writing assistance.
“There are two sides of the story,” Dr. El Bairi said. “The good side is that unfortunately, sometimes [industry money is] the only way for African oncologists to go abroad for training, to conferences for their continuous medical education. The bad is now we may harm patients, we might harm science by having conflicts of interest not reported.”
Unlike other countries, the United States has plentiful data on the scale of physicians’ financial conflicts of interest in the form of the Open Payments platform. Championed by Sen. Chuck Grassley (R-Iowa), the federal repository of payments to doctors and teaching hospitals by drug and medical device companies was established as part of the Affordable Care Act (ACA).
The health care reform law, which passed in 2010, requires pharmaceutical companies and medical device makers to report this information.
From 2013 to 2021, the pharmaceutical and medical device industry paid physicians $12.1 billion, according to a research letter published in JAMA in March of 2024 that reviewed Open Payments data.
Ranked by specialty, hematologists and oncologists received the fourth-largest amount of money in aggregate, the study shows. Their total of $825.8 million trailed only physicians in orthopedics ($1.36 billion), neurology and psychiatry ($1.32 billion) and cardiology ($1.29 billion). What’s more, this specialty had the biggest share of physicians taking industry money, with 74.2% of hematologists and oncologists receiving payments.
The payments from industry include fees for consulting services and speaking, as well as food and beverages, travel and lodging, education, gifts, grants, and honoraria.
Joseph S. Ross, MD, MHS, one of the JAMA study’s coauthors, said in an interview that the continued prevalence of such funding runs counter to the expectation behind the measure, which was that transparency would lead to physicians’ becoming less likely to accept a payment.
“We as a profession need to take a cold hard look in the mirror,” he said, referring to physicians in general.
Dr. Ross, professor of medicine at Yale University School of Medicine, New Haven, Connecticut, said he hopes that the profession will self-police, and that patients will make a bigger deal of the issue. Still, he acknowledged that “the vast majority” of patient advocacy groups, too, are funded by the pharmaceutical industry.
Exposing Industry Payments May Have Perverse Effect
A growing body of research explores the effect that physicians’ financial relationships with pharmaceutical companies can have on their prescribing practices. Indeed, oncologists taking industry payments seem to be more likely to prescribe nonrecommended and low-value drugs in some clinical settings, according to a study published in The BMJ last year.
That study’s first author, Aaron P. Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center, New York City, suggested in an interview that exposing industry payments to the sunlight may have had a perverse effect on physicians.
“There’s this idea of having license to do something,” Dr. Mitchell said, speaking broadly about human psychology rather than drawing on empirical data. “You might feel a little less bad about then prescribing more of that company’s drug, because the disclosure has already been done.”
The influence of pharmaceutical industry money on oncologists goes beyond what’s prescribed to which treatments get studied, approved, and recommended by guidelines, Dr. Mitchell said. He was also first author of a 2016 paper published in JAMA Oncology that found 86% of authors of the National Comprehensive Cancer Network guidelines had at least one conflict of interest reported on Open Systems in 2014.
Meanwhile, the fact that physicians’ payments from industry are a matter of public record on Open Systems has not guaranteed that doctors will disclose their conflicts of interest in other forums. A study published in JAMA earlier this year, for which Dr. Mitchell served as first author, found that almost one in three physicians endorsing drugs and devices on the social media platform X failed to disclose that the manufacturer paid them.
The lack of disclosure seems to extend beyond social media. A 2018 study published in JAMA Oncology found that 32% of oncologist authors of clinical drug trials for drugs approved over a 20-month period from 2016 to 2017 did not fully disclose payments from the trial sponsor when checked against the Open Payments database.
A lion’s share of industry payments within oncology appears to be going to a small group of high-profile physicians, suggested a 2022 study published in JCO Oncology Practice. It found that just 1% of all US oncologists accounted for 37% of industry payments, with each receiving more than $100,000 a year.
Experts: Professional Societies Should Further Limit Industry Payments
While partnerships between drug companies and physicians are necessary and have often been positive, more than disclosure is needed to minimize the risk of patient harm, according to an editorial published in March in JCO Oncology Practice. In it, Nina Niu Sanford, MD, a radiation oncologist UT Southwestern Medical Center, Dallas, and Bishal Gyawali, MD, PhD, a medical oncologist at Queen’s University, Kingston, Ontario, Canada, argue that following a specific blueprint could help mitigate financial conflicts of interest.
For starters, Dr. Sanford and Dr. Gyawali contend in the editorial that the maximum general payment NCCN members are allowed to receive from industry should be $0, compared with a current bar of $20,000 from a single entity or $50,000 from all external entities combined. They also urge professional societies to follow the current policy of the American Society of Clinical Oncology and ban members serving in their leadership from receiving any general payments from the industry.
The authors further suggest that investigators of clinical trials should be barred from holding stock for the drug or product while it is under study and that editorialists should not have conflicts of interest with the company whose drug or product they are discussing.
Pharmaceutical money can harm patients in ways that are not always obvious, Dr. Gyawali said in an interview.
“It can dominate the conversation by removing critical viewpoints from these top people about certain drugs,” he said. “It’s not always about saying good things about the drug.”
For instance, he suggested, a doctor receiving payments from Pfizer might openly criticize perceived flaws in drugs from other companies but refrain from weighing in negatively on a Pfizer drug.
From 2016 to 2018, industry made general payments to more than 52,000 physicians for 137 unique cancer drugs, according to a separate 2021 study published in the Journal of Cancer Policy, for which Dr. Gyawali served as one of the coauthors.
The results suggest that pharmaceutical money affects the entire cancer system, not relatively few oncology leaders. The amounts and dollar values grew each year covered by the study, to nearly 466,000 payments totaling $98.5 million in 2018.
Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, Washington, DC, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices, has called for a ban on industry gifts to physicians.
When a publication asks physicians to disclose relevant conflicts of interest, physicians may choose not to disclose, because they don’t feel that their conflicts are relevant, Dr. Fugh-Berman said. Drug and device makers have also grown sophisticated about how they work with physicians, she suggested. “It’s illegal to market a drug before it comes on the market, but it’s not illegal to market the disease,” said Dr. Fugh-Berman, noting that drugmakers often work on long timelines.
“The doctor is going around saying we don’t have good therapies. They’re not pushing a drug. And so they feel totally fine about it.”
Anecdotally, Dr. Fugh-Berman noted that, if anything, speaking fees and similar payments only improve doctors’ reputations. She said that’s especially true if the physicians are paid by multiple companies, on the supposed theory that their conflicts of interest cancel each other out.
“I’m not defending this,” added Dr. Fugh-Berman, observing that, at the end of the day, such conflicts may go against the interests of patients.
“Sometimes the best drugs are older, generic, cheap drugs, and if oncologists or other specialists are only choosing among the most promoted drugs, they’re not necessarily choosing the best drugs.”
Beyond any prestige, doctors have other possible nonfinancial incentives for receiving industry payments. “It’s the relationships,” Dr. Fugh-Berman said. “Companies are very good at offering friendship.”
Dr. El Bairi reported NCODA leadership and honoraria along with expert testimony through techspert.io. Dr. Ross reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of or the review of the manuscript he authored and discussed in this article. Dr. Ross also reported receiving grants from the Food and Drug Administration, Johnson & Johnson, the Medical Device Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Mitchell reported no relevant financial relationships. Dr. Gyawali reported a consulting or advisory role with Vivio Health. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.
FROM ASCO 2024
Munchausen Syndrome by Proxy: Be Aware of Cutaneous Signs
TORONTO — Be suspicious if a child with a severe dermatologic condition is unresponsive to treatment, especially if their parent or caregiver exhibits deceptive behavior.
These could be red flags for Munchausen syndrome by proxy (MSBP), also known as factitious disorder.
“The No. 1 thing dermatologists can do in situations like this is be open to thinking outside the box and ask themselves the difficult question: Could this be something the parent is inflicting on the child,” Kelly Frasier, DO, a dermatology clinical trials and epidemiology research fellow at Northwell Health, Poughkeepsie, New York, said in an interview.
She provided a review on advancing the understanding of the dermatologic manifestations of MSBP during a poster session at the annual meeting of the Society for Pediatric Dermatology (SPD). Dr. Frasier has a particular interest in psychodermatology — she was a mental health therapist before going to medical school.
MSBP is a type of abuse intentionally inflicted by a caregiver typically on their child “for some ulterior motive,” usually to seek attention or sympathy and not for material or financial gain, explained Dr. Frasier. People with MSBP seek medical help for exaggerated or fabricated symptoms in their child. They may alter medical tests, falsify medical records, or induce symptoms in their child.
To do this, these abusers may apply any number of caustic household products, including glue, directly to the child’s skin or even in formula. Dr. Frasier shared a picture of a baby whose formula had been doctored with a caustic substance that had dripped onto his neck and face, causing a rash with blisters.
In addition to blistering, cutaneous manifestations of MSBP can include severe bruising. Or the child may present with signs similar to those of granuloma annulare (a benign condition characterized by small, raised bumps) or cicatricial pemphigoid (a rare, chronic autoimmune blistering disorder) or may have recurrent nail avulsion, purpura, or coagulopathy, said Dr. Frasier.
In almost all cases of MSBP (an estimated 96%), the abuse is inflicted by the mother, who may have a preexisting mental illness. “Usually, a psychological disorder is at play, such as depression or anxiety,” said Dr. Frasier.
Some evidence suggests that, in cases of MSBP, the caregiver may have a personality disorder such as borderline or histrionic personality disorder — or may have suffered abuse or neglect as a child or is experiencing major stress, which some evidence suggests can trigger MSPB, she added.
This type of abuse is rarely seen in children older than 6 years, likely because they get wise to what’s going on and are better able to fight back or resist as they get older, Dr. Fraser noted.
High Mortality Rate
It’s critical that cases of MSBP are identified early. While a small proportion of child abuse cases involve MSBP, the mortality rate is extremely high, about 10%, research suggests, said Dr. Frasier.
Dermatologists should be skeptical if the child’s condition hasn’t improved despite trying numerous treatments that normally would have some effect. “If you’re doing everything you can to treat something that’s usually pretty simple in terms of what you normally see clinically and how you treat it, and you’re not seeing any improvement or things continue to get worse, that’s definitely a sign something else may be going on,” Dr. Frasier said.
Another suspicious sign is inflammation that continues “for weeks or months” and “doesn’t match up with actual lab markers and lab values,” said Dr. Frasier.
Other signs of possible MSBP include evidence of chemicals in the child’s blood, stool, or urine, or the child’s condition improves while in the hospital, but symptoms return after returning home.
Also be aware of the interaction between the parent and child, said Dr. Frasier. “See if you can pick up that something else might be going on, especially if the symptoms aren’t lining up very well with what you’re physically seeing and what your clinical impression is.”
And be suspicious of a parent’s inappropriate behavior; for example, they seem to be deliberately making symptoms worse or appear overly distraught. The seemingly caring parent could be overcompensating for what she’s doing at home, “and she wants to make sure it doesn’t appear that way,” said Dr. Frasier.
To help determine if some sort of trauma is occurring at home, the child would ideally be separated from the caregiver, perhaps with a nurse or other member of the interdisciplinary medical team, Dr. Frasier said.
It appears that pediatric dermatologists are already aware of the importance of protecting children from abuse. During a presentation at the meeting on child abuse and maltreatment in dermatology, not specifically on MSBP, Romy Cho, MD, assistant professor, Department of Pediatrics, University of Toronto, who is involved with the SCAN Program at The Hospital for Sick Children, Toronto, Canada, polled the audience on whether they had ever contacted child protective services (CPS). Almost 80% said they had.
That’s good news for Dr. Frasier. “We have to be willing to contact CPS if we think there’s something going on, and be more open to that because it’s better to be safe than sorry, especially in cases involving children.”
Dr. Frasier and Dr. Cho had no relevant disclosures.
A version of this article first appeared on Medscape.com.
TORONTO — Be suspicious if a child with a severe dermatologic condition is unresponsive to treatment, especially if their parent or caregiver exhibits deceptive behavior.
These could be red flags for Munchausen syndrome by proxy (MSBP), also known as factitious disorder.
“The No. 1 thing dermatologists can do in situations like this is be open to thinking outside the box and ask themselves the difficult question: Could this be something the parent is inflicting on the child,” Kelly Frasier, DO, a dermatology clinical trials and epidemiology research fellow at Northwell Health, Poughkeepsie, New York, said in an interview.
She provided a review on advancing the understanding of the dermatologic manifestations of MSBP during a poster session at the annual meeting of the Society for Pediatric Dermatology (SPD). Dr. Frasier has a particular interest in psychodermatology — she was a mental health therapist before going to medical school.
MSBP is a type of abuse intentionally inflicted by a caregiver typically on their child “for some ulterior motive,” usually to seek attention or sympathy and not for material or financial gain, explained Dr. Frasier. People with MSBP seek medical help for exaggerated or fabricated symptoms in their child. They may alter medical tests, falsify medical records, or induce symptoms in their child.
To do this, these abusers may apply any number of caustic household products, including glue, directly to the child’s skin or even in formula. Dr. Frasier shared a picture of a baby whose formula had been doctored with a caustic substance that had dripped onto his neck and face, causing a rash with blisters.
In addition to blistering, cutaneous manifestations of MSBP can include severe bruising. Or the child may present with signs similar to those of granuloma annulare (a benign condition characterized by small, raised bumps) or cicatricial pemphigoid (a rare, chronic autoimmune blistering disorder) or may have recurrent nail avulsion, purpura, or coagulopathy, said Dr. Frasier.
In almost all cases of MSBP (an estimated 96%), the abuse is inflicted by the mother, who may have a preexisting mental illness. “Usually, a psychological disorder is at play, such as depression or anxiety,” said Dr. Frasier.
Some evidence suggests that, in cases of MSBP, the caregiver may have a personality disorder such as borderline or histrionic personality disorder — or may have suffered abuse or neglect as a child or is experiencing major stress, which some evidence suggests can trigger MSPB, she added.
This type of abuse is rarely seen in children older than 6 years, likely because they get wise to what’s going on and are better able to fight back or resist as they get older, Dr. Fraser noted.
High Mortality Rate
It’s critical that cases of MSBP are identified early. While a small proportion of child abuse cases involve MSBP, the mortality rate is extremely high, about 10%, research suggests, said Dr. Frasier.
Dermatologists should be skeptical if the child’s condition hasn’t improved despite trying numerous treatments that normally would have some effect. “If you’re doing everything you can to treat something that’s usually pretty simple in terms of what you normally see clinically and how you treat it, and you’re not seeing any improvement or things continue to get worse, that’s definitely a sign something else may be going on,” Dr. Frasier said.
Another suspicious sign is inflammation that continues “for weeks or months” and “doesn’t match up with actual lab markers and lab values,” said Dr. Frasier.
Other signs of possible MSBP include evidence of chemicals in the child’s blood, stool, or urine, or the child’s condition improves while in the hospital, but symptoms return after returning home.
Also be aware of the interaction between the parent and child, said Dr. Frasier. “See if you can pick up that something else might be going on, especially if the symptoms aren’t lining up very well with what you’re physically seeing and what your clinical impression is.”
And be suspicious of a parent’s inappropriate behavior; for example, they seem to be deliberately making symptoms worse or appear overly distraught. The seemingly caring parent could be overcompensating for what she’s doing at home, “and she wants to make sure it doesn’t appear that way,” said Dr. Frasier.
To help determine if some sort of trauma is occurring at home, the child would ideally be separated from the caregiver, perhaps with a nurse or other member of the interdisciplinary medical team, Dr. Frasier said.
It appears that pediatric dermatologists are already aware of the importance of protecting children from abuse. During a presentation at the meeting on child abuse and maltreatment in dermatology, not specifically on MSBP, Romy Cho, MD, assistant professor, Department of Pediatrics, University of Toronto, who is involved with the SCAN Program at The Hospital for Sick Children, Toronto, Canada, polled the audience on whether they had ever contacted child protective services (CPS). Almost 80% said they had.
That’s good news for Dr. Frasier. “We have to be willing to contact CPS if we think there’s something going on, and be more open to that because it’s better to be safe than sorry, especially in cases involving children.”
Dr. Frasier and Dr. Cho had no relevant disclosures.
A version of this article first appeared on Medscape.com.
TORONTO — Be suspicious if a child with a severe dermatologic condition is unresponsive to treatment, especially if their parent or caregiver exhibits deceptive behavior.
These could be red flags for Munchausen syndrome by proxy (MSBP), also known as factitious disorder.
“The No. 1 thing dermatologists can do in situations like this is be open to thinking outside the box and ask themselves the difficult question: Could this be something the parent is inflicting on the child,” Kelly Frasier, DO, a dermatology clinical trials and epidemiology research fellow at Northwell Health, Poughkeepsie, New York, said in an interview.
She provided a review on advancing the understanding of the dermatologic manifestations of MSBP during a poster session at the annual meeting of the Society for Pediatric Dermatology (SPD). Dr. Frasier has a particular interest in psychodermatology — she was a mental health therapist before going to medical school.
MSBP is a type of abuse intentionally inflicted by a caregiver typically on their child “for some ulterior motive,” usually to seek attention or sympathy and not for material or financial gain, explained Dr. Frasier. People with MSBP seek medical help for exaggerated or fabricated symptoms in their child. They may alter medical tests, falsify medical records, or induce symptoms in their child.
To do this, these abusers may apply any number of caustic household products, including glue, directly to the child’s skin or even in formula. Dr. Frasier shared a picture of a baby whose formula had been doctored with a caustic substance that had dripped onto his neck and face, causing a rash with blisters.
In addition to blistering, cutaneous manifestations of MSBP can include severe bruising. Or the child may present with signs similar to those of granuloma annulare (a benign condition characterized by small, raised bumps) or cicatricial pemphigoid (a rare, chronic autoimmune blistering disorder) or may have recurrent nail avulsion, purpura, or coagulopathy, said Dr. Frasier.
In almost all cases of MSBP (an estimated 96%), the abuse is inflicted by the mother, who may have a preexisting mental illness. “Usually, a psychological disorder is at play, such as depression or anxiety,” said Dr. Frasier.
Some evidence suggests that, in cases of MSBP, the caregiver may have a personality disorder such as borderline or histrionic personality disorder — or may have suffered abuse or neglect as a child or is experiencing major stress, which some evidence suggests can trigger MSPB, she added.
This type of abuse is rarely seen in children older than 6 years, likely because they get wise to what’s going on and are better able to fight back or resist as they get older, Dr. Fraser noted.
High Mortality Rate
It’s critical that cases of MSBP are identified early. While a small proportion of child abuse cases involve MSBP, the mortality rate is extremely high, about 10%, research suggests, said Dr. Frasier.
Dermatologists should be skeptical if the child’s condition hasn’t improved despite trying numerous treatments that normally would have some effect. “If you’re doing everything you can to treat something that’s usually pretty simple in terms of what you normally see clinically and how you treat it, and you’re not seeing any improvement or things continue to get worse, that’s definitely a sign something else may be going on,” Dr. Frasier said.
Another suspicious sign is inflammation that continues “for weeks or months” and “doesn’t match up with actual lab markers and lab values,” said Dr. Frasier.
Other signs of possible MSBP include evidence of chemicals in the child’s blood, stool, or urine, or the child’s condition improves while in the hospital, but symptoms return after returning home.
Also be aware of the interaction between the parent and child, said Dr. Frasier. “See if you can pick up that something else might be going on, especially if the symptoms aren’t lining up very well with what you’re physically seeing and what your clinical impression is.”
And be suspicious of a parent’s inappropriate behavior; for example, they seem to be deliberately making symptoms worse or appear overly distraught. The seemingly caring parent could be overcompensating for what she’s doing at home, “and she wants to make sure it doesn’t appear that way,” said Dr. Frasier.
To help determine if some sort of trauma is occurring at home, the child would ideally be separated from the caregiver, perhaps with a nurse or other member of the interdisciplinary medical team, Dr. Frasier said.
It appears that pediatric dermatologists are already aware of the importance of protecting children from abuse. During a presentation at the meeting on child abuse and maltreatment in dermatology, not specifically on MSBP, Romy Cho, MD, assistant professor, Department of Pediatrics, University of Toronto, who is involved with the SCAN Program at The Hospital for Sick Children, Toronto, Canada, polled the audience on whether they had ever contacted child protective services (CPS). Almost 80% said they had.
That’s good news for Dr. Frasier. “We have to be willing to contact CPS if we think there’s something going on, and be more open to that because it’s better to be safe than sorry, especially in cases involving children.”
Dr. Frasier and Dr. Cho had no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM SPD 2024
More Illnesses Possible Related Linked to Counterfeit Botulinum Toxin Reported
— two in the intensive care unit. None of the cases required intubation, according to an announcement of an investigation into these reports in by the Centers for Disease Control and Prevention (CDC).
The report, published online in the Morbidity and Mortality Weekly Report, notes that the four patients in Tennessee received counterfeit BoNT, while product information was not available for the three cases in New York City. “However, one person reported paying less than US wholesale acquisition cost for the administered product, and another reported that the product had been purchased overseas,” the authors of the report wrote. The development underscores that BoNT injections “should be administered only by licensed and trained providers using recommended doses of FDA [Food and Drug Admininstration]-approved products.”
This report follows a CDC advisory published in April 2024 of at least 22 people from 11 states who reported serious reactions after receiving botulinum toxin injections from unlicensed or untrained individuals or in nonhealthcare settings, such as homes and spas.
The median age of the women in the July report was 48 years, and signs and symptoms included ptosis, dry mouth, dysphagia, shortness of breath, and weakness. Onset occurred between February 23 and March 7, 2024.
“This investigation did not determine why these illnesses occurred after cosmetic BoNT injections; potential reasons might include use of counterfeit BoNT, which might be more potent or contain harmful additional ingredients or higher susceptibility to BoNT effects among some persons,” the investigators wrote. They recommended further studies to describe the clinical spectrum of cosmetic BoNT injection effects such as severity of signs and symptoms.
For cases of suspected systemic botulism, the CDC recommends calling the local or state health department for consultation and antitoxin release (as well as information on reporting adverse events). Alternatively, the 24/7 phone number for the CDC clinical botulism service is 770-488-7100.
A version of this article first appeared on Medscape.com.
— two in the intensive care unit. None of the cases required intubation, according to an announcement of an investigation into these reports in by the Centers for Disease Control and Prevention (CDC).
The report, published online in the Morbidity and Mortality Weekly Report, notes that the four patients in Tennessee received counterfeit BoNT, while product information was not available for the three cases in New York City. “However, one person reported paying less than US wholesale acquisition cost for the administered product, and another reported that the product had been purchased overseas,” the authors of the report wrote. The development underscores that BoNT injections “should be administered only by licensed and trained providers using recommended doses of FDA [Food and Drug Admininstration]-approved products.”
This report follows a CDC advisory published in April 2024 of at least 22 people from 11 states who reported serious reactions after receiving botulinum toxin injections from unlicensed or untrained individuals or in nonhealthcare settings, such as homes and spas.
The median age of the women in the July report was 48 years, and signs and symptoms included ptosis, dry mouth, dysphagia, shortness of breath, and weakness. Onset occurred between February 23 and March 7, 2024.
“This investigation did not determine why these illnesses occurred after cosmetic BoNT injections; potential reasons might include use of counterfeit BoNT, which might be more potent or contain harmful additional ingredients or higher susceptibility to BoNT effects among some persons,” the investigators wrote. They recommended further studies to describe the clinical spectrum of cosmetic BoNT injection effects such as severity of signs and symptoms.
For cases of suspected systemic botulism, the CDC recommends calling the local or state health department for consultation and antitoxin release (as well as information on reporting adverse events). Alternatively, the 24/7 phone number for the CDC clinical botulism service is 770-488-7100.
A version of this article first appeared on Medscape.com.
— two in the intensive care unit. None of the cases required intubation, according to an announcement of an investigation into these reports in by the Centers for Disease Control and Prevention (CDC).
The report, published online in the Morbidity and Mortality Weekly Report, notes that the four patients in Tennessee received counterfeit BoNT, while product information was not available for the three cases in New York City. “However, one person reported paying less than US wholesale acquisition cost for the administered product, and another reported that the product had been purchased overseas,” the authors of the report wrote. The development underscores that BoNT injections “should be administered only by licensed and trained providers using recommended doses of FDA [Food and Drug Admininstration]-approved products.”
This report follows a CDC advisory published in April 2024 of at least 22 people from 11 states who reported serious reactions after receiving botulinum toxin injections from unlicensed or untrained individuals or in nonhealthcare settings, such as homes and spas.
The median age of the women in the July report was 48 years, and signs and symptoms included ptosis, dry mouth, dysphagia, shortness of breath, and weakness. Onset occurred between February 23 and March 7, 2024.
“This investigation did not determine why these illnesses occurred after cosmetic BoNT injections; potential reasons might include use of counterfeit BoNT, which might be more potent or contain harmful additional ingredients or higher susceptibility to BoNT effects among some persons,” the investigators wrote. They recommended further studies to describe the clinical spectrum of cosmetic BoNT injection effects such as severity of signs and symptoms.
For cases of suspected systemic botulism, the CDC recommends calling the local or state health department for consultation and antitoxin release (as well as information on reporting adverse events). Alternatively, the 24/7 phone number for the CDC clinical botulism service is 770-488-7100.
A version of this article first appeared on Medscape.com.
FROM THE MMWR
Study Detects Bacteria in Tattoo, Permanent Makeup Inks
When US researchers tested 75 unopened and sealed tattoo and permanent makeup inks from 14 different manufacturers, they discovered that about 35% of the products were contaminated with bacteria.
They detected both aerobic bacteria and anaerobic bacteria, which thrive in low-oxygen environments like the dermal layer of the skin.
“This suggests that contaminated tattoo inks could be a source of infection from both types of bacteria,” Seong-Jae Peter Kim, PhD, a microbiologist with the Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, who worked on the study, said in a news release.
The findings “are concerning,” said Waleed Javaid, MD, professor of medicine and director of infection prevention and control for the Mount Sinai Health System in New York City. “This contamination poses a significant health risk, as these inks are injected into the dermal layer of the skin, creating an environment conducive to bacterial infections,” said Dr. Javaid, who wasn’t involved in the study, which was published online in Applied and Environmental Microbiology.
New Body Art Culture
Tattoos are more popular than ever, and it is estimated that at least 32% of people in the United States have at least one tattoo. And the rise in popularity has coincided with an increase in ink-related infections.
This new research joins previous studies that have demonstrated that commercial tattoo and permanent makeup inks are often contaminated with pathogenic microorganisms.
Of the 75 ink samples that Dr. Kim and colleagues tested, 26 were contaminated with 34 bacterial isolates classified into 14 genera and 22 species. Among the 34 bacterial isolates, 19 were identified as possibly pathogenic bacterial strains.
Two species — Cutibacterium acnes (four strains) and Staphylococcus epidermidis (two strains) — were isolated under anaerobic conditions.
Two possibly pathogenic bacterial strains — Staphylococcus saprophyticus and C acnes — were isolated from the same two ink samples, indicating that tattoo and permanent makeup inks can harbor both aerobic (S saprophyticus) and anaerobic (C acnes) bacteria.
There was no significant association between sterility claims on the ink label and the absence of bacterial contamination.
“The presence of bacteria like Cutibacterium acnes and Staphylococcus epidermidis, which can cause skin infections and other complications, underscores the potential danger to individuals receiving tattoos or permanent makeup,” Dr. Javaid explained.
The results “emphasize the importance of monitoring these products for both aerobic and anaerobic bacteria, including possibly pathogenic microorganisms,” Dr. Kim said in the news release.
The next steps, according to the researchers, include developing more efficient and accurate microbial detection methods for tattoo inks to streamline the monitoring process and examining the occurrence, co-occurrence, and diversity of microbial contaminants in tattoo inks to prevent future contamination.
Counseling Patients
Healthcare professionals play a “crucial role in counseling patients about the risks associated with tattoos. They should inform patients about the potential for infections, allergic reactions, and other complications related to tattooing and permanent ink,” said Dr. Javaid.
Specific advice can include ensuring that the tattoo parlor adheres to strict hygiene practices and verifying that tattoo inks are from reputable sources and, if possible, have undergone sterilization.
Clinicians should discuss the importance of proper aftercare to minimize the risk for infection, recommend patients with compromised immune systems or skin conditions to reconsider getting a tattoo, and encourage patients to be aware of the signs of infection and to seek medical attention promptly if any symptoms arise.
“Enhanced regulatory measures would help reduce the risk of infections and ensure safer tattooing practices for consumers,” Dr. Javaid said. The findings of Dr. Kim and colleagues “indicate that current manufacturing and sterilization processes are inadequate.”
Regulations could include stricter manufacturing standards to ensure sterility, the mandatory testing of inks for microbial contamination before they reach the market, clear labeling requirements that accurately reflect the sterility and safety of products, and regular inspections and audits of tattoo ink manufacturers, he said, which could encourage the development of more effective sterilization techniques to eliminate bacterial contamination.
The FDA has created a document — Think Before You Ink: Tattoo Safety — for consumers who are considering getting a tattoo.
A version of this article first appeared on Medscape.com.
When US researchers tested 75 unopened and sealed tattoo and permanent makeup inks from 14 different manufacturers, they discovered that about 35% of the products were contaminated with bacteria.
They detected both aerobic bacteria and anaerobic bacteria, which thrive in low-oxygen environments like the dermal layer of the skin.
“This suggests that contaminated tattoo inks could be a source of infection from both types of bacteria,” Seong-Jae Peter Kim, PhD, a microbiologist with the Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, who worked on the study, said in a news release.
The findings “are concerning,” said Waleed Javaid, MD, professor of medicine and director of infection prevention and control for the Mount Sinai Health System in New York City. “This contamination poses a significant health risk, as these inks are injected into the dermal layer of the skin, creating an environment conducive to bacterial infections,” said Dr. Javaid, who wasn’t involved in the study, which was published online in Applied and Environmental Microbiology.
New Body Art Culture
Tattoos are more popular than ever, and it is estimated that at least 32% of people in the United States have at least one tattoo. And the rise in popularity has coincided with an increase in ink-related infections.
This new research joins previous studies that have demonstrated that commercial tattoo and permanent makeup inks are often contaminated with pathogenic microorganisms.
Of the 75 ink samples that Dr. Kim and colleagues tested, 26 were contaminated with 34 bacterial isolates classified into 14 genera and 22 species. Among the 34 bacterial isolates, 19 were identified as possibly pathogenic bacterial strains.
Two species — Cutibacterium acnes (four strains) and Staphylococcus epidermidis (two strains) — were isolated under anaerobic conditions.
Two possibly pathogenic bacterial strains — Staphylococcus saprophyticus and C acnes — were isolated from the same two ink samples, indicating that tattoo and permanent makeup inks can harbor both aerobic (S saprophyticus) and anaerobic (C acnes) bacteria.
There was no significant association between sterility claims on the ink label and the absence of bacterial contamination.
“The presence of bacteria like Cutibacterium acnes and Staphylococcus epidermidis, which can cause skin infections and other complications, underscores the potential danger to individuals receiving tattoos or permanent makeup,” Dr. Javaid explained.
The results “emphasize the importance of monitoring these products for both aerobic and anaerobic bacteria, including possibly pathogenic microorganisms,” Dr. Kim said in the news release.
The next steps, according to the researchers, include developing more efficient and accurate microbial detection methods for tattoo inks to streamline the monitoring process and examining the occurrence, co-occurrence, and diversity of microbial contaminants in tattoo inks to prevent future contamination.
Counseling Patients
Healthcare professionals play a “crucial role in counseling patients about the risks associated with tattoos. They should inform patients about the potential for infections, allergic reactions, and other complications related to tattooing and permanent ink,” said Dr. Javaid.
Specific advice can include ensuring that the tattoo parlor adheres to strict hygiene practices and verifying that tattoo inks are from reputable sources and, if possible, have undergone sterilization.
Clinicians should discuss the importance of proper aftercare to minimize the risk for infection, recommend patients with compromised immune systems or skin conditions to reconsider getting a tattoo, and encourage patients to be aware of the signs of infection and to seek medical attention promptly if any symptoms arise.
“Enhanced regulatory measures would help reduce the risk of infections and ensure safer tattooing practices for consumers,” Dr. Javaid said. The findings of Dr. Kim and colleagues “indicate that current manufacturing and sterilization processes are inadequate.”
Regulations could include stricter manufacturing standards to ensure sterility, the mandatory testing of inks for microbial contamination before they reach the market, clear labeling requirements that accurately reflect the sterility and safety of products, and regular inspections and audits of tattoo ink manufacturers, he said, which could encourage the development of more effective sterilization techniques to eliminate bacterial contamination.
The FDA has created a document — Think Before You Ink: Tattoo Safety — for consumers who are considering getting a tattoo.
A version of this article first appeared on Medscape.com.
When US researchers tested 75 unopened and sealed tattoo and permanent makeup inks from 14 different manufacturers, they discovered that about 35% of the products were contaminated with bacteria.
They detected both aerobic bacteria and anaerobic bacteria, which thrive in low-oxygen environments like the dermal layer of the skin.
“This suggests that contaminated tattoo inks could be a source of infection from both types of bacteria,” Seong-Jae Peter Kim, PhD, a microbiologist with the Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, who worked on the study, said in a news release.
The findings “are concerning,” said Waleed Javaid, MD, professor of medicine and director of infection prevention and control for the Mount Sinai Health System in New York City. “This contamination poses a significant health risk, as these inks are injected into the dermal layer of the skin, creating an environment conducive to bacterial infections,” said Dr. Javaid, who wasn’t involved in the study, which was published online in Applied and Environmental Microbiology.
New Body Art Culture
Tattoos are more popular than ever, and it is estimated that at least 32% of people in the United States have at least one tattoo. And the rise in popularity has coincided with an increase in ink-related infections.
This new research joins previous studies that have demonstrated that commercial tattoo and permanent makeup inks are often contaminated with pathogenic microorganisms.
Of the 75 ink samples that Dr. Kim and colleagues tested, 26 were contaminated with 34 bacterial isolates classified into 14 genera and 22 species. Among the 34 bacterial isolates, 19 were identified as possibly pathogenic bacterial strains.
Two species — Cutibacterium acnes (four strains) and Staphylococcus epidermidis (two strains) — were isolated under anaerobic conditions.
Two possibly pathogenic bacterial strains — Staphylococcus saprophyticus and C acnes — were isolated from the same two ink samples, indicating that tattoo and permanent makeup inks can harbor both aerobic (S saprophyticus) and anaerobic (C acnes) bacteria.
There was no significant association between sterility claims on the ink label and the absence of bacterial contamination.
“The presence of bacteria like Cutibacterium acnes and Staphylococcus epidermidis, which can cause skin infections and other complications, underscores the potential danger to individuals receiving tattoos or permanent makeup,” Dr. Javaid explained.
The results “emphasize the importance of monitoring these products for both aerobic and anaerobic bacteria, including possibly pathogenic microorganisms,” Dr. Kim said in the news release.
The next steps, according to the researchers, include developing more efficient and accurate microbial detection methods for tattoo inks to streamline the monitoring process and examining the occurrence, co-occurrence, and diversity of microbial contaminants in tattoo inks to prevent future contamination.
Counseling Patients
Healthcare professionals play a “crucial role in counseling patients about the risks associated with tattoos. They should inform patients about the potential for infections, allergic reactions, and other complications related to tattooing and permanent ink,” said Dr. Javaid.
Specific advice can include ensuring that the tattoo parlor adheres to strict hygiene practices and verifying that tattoo inks are from reputable sources and, if possible, have undergone sterilization.
Clinicians should discuss the importance of proper aftercare to minimize the risk for infection, recommend patients with compromised immune systems or skin conditions to reconsider getting a tattoo, and encourage patients to be aware of the signs of infection and to seek medical attention promptly if any symptoms arise.
“Enhanced regulatory measures would help reduce the risk of infections and ensure safer tattooing practices for consumers,” Dr. Javaid said. The findings of Dr. Kim and colleagues “indicate that current manufacturing and sterilization processes are inadequate.”
Regulations could include stricter manufacturing standards to ensure sterility, the mandatory testing of inks for microbial contamination before they reach the market, clear labeling requirements that accurately reflect the sterility and safety of products, and regular inspections and audits of tattoo ink manufacturers, he said, which could encourage the development of more effective sterilization techniques to eliminate bacterial contamination.
The FDA has created a document — Think Before You Ink: Tattoo Safety — for consumers who are considering getting a tattoo.
A version of this article first appeared on Medscape.com.
FROM APPLIED AND ENVIRONMENTAL MICROBIOLOGY
For Richer, for Poorer: Low-Carb Diets Work for All Incomes
For 3 years, Ajala Efem’s type 2 diabetes was so poorly controlled that her blood sugar often soared northward of 500 mg/dL despite insulin shots three to five times a day. She would experience dizziness, vomiting, severe headaches, and the neuropathy in her feet made walking painful. She was also — literally — frothing at the mouth. The 47-year-old single mother of two adult children with mental disabilities feared that she would die.
Ms. Efem lives in the South Bronx, which is among the poorest areas of New York City, where the combined rate of prediabetes and diabetes is close to 30%, the highest rate of any borough in the city.
She had to wait 8 months for an appointment with an endocrinologist, but that visit proved to be life-changing. She lost 28 pounds and got off 15 medications in a single month. She did not join a gym or count calories; she simply changed the food she ate and adopted a low-carb diet.
“I went from being sick to feeling so great,” she told her endocrinologist recently: “My feet aren’t hurting; I’m not in pain; I’m eating as much as I want, and I really enjoy my food so much.”
Ms. Efem’s life-changing visit was with Mariela Glandt, MD, at the offices of Essen Health Care. One month earlier, Dr. Glandt’s company, OwnaHealth, was contracted by Essen to conduct a 100-person pilot program for endocrinology patients. Essen is the largest Medicaid provider in New York City, and “they were desperate for an endocrinologist,” said Dr. Glandt, who trained at Columbia University in New York. So she came — all the way from Madrid, Spain. She commutes monthly, staying for a week each visit.
Dr. Glandt keeps up this punishing schedule because, as she explains, “it’s such a high for me to see these incredible transformations.” Her mostly Black and Hispanic patients are poor and lack resources, yet they lose significant amounts of weight, and their health issues resolve.
“Food is medicine” is an idea very much in vogue. The concept was central to the landmark White House Conference on Hunger, Nutrition, and Health in 2022 and is now the focus of a number of a wide range of government programs. Recently, the Senate held a hearing aimed at further expanding food as medicine programs.
Still, only a single randomized controlled clinical trial has been conducted on this nutritional approach, with unexpectedly disappointing results. In the mid-Atlantic region, 456 food-insecure adults with type 2 diabetes were randomly assigned to usual care or the provision of weekly groceries for their entire families for about 1 year. Provisions for a Mediterranean-style diet included whole grains, fruits and vegetables, lean protein, low-fat dairy products, cereal, brown rice, and bread. In addition, participants received dietary consultations. Yet, those who got free food and coaching did not see improvements in their average blood sugar (the study’s primary outcome), and their low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels appeared to have worsened.
“To be honest, I was surprised,” the study’s lead author, Joseph Doyle, PhD, professor at the Sloan School of Management at MIT in Cambridge, Massachusetts, told me. “I was hoping we would show improved outcomes, but the way to make progress is to do well-randomized trials to find out what works.”
I was not surprised by these results because a recent rigorous systematic review and meta-analysis in The BMJ did not show a Mediterranean-style diet to be the most effective for glycemic control. And Ms. Efem was not in fact following a Mediterranean-style diet.
Ms. Efem’s low-carb success story is anecdotal, but Dr. Glandt has an established track record from her 9 years’ experience as the medical director of the eponymous diabetes center she founded in Tel Aviv. A recent audit of 344 patients from the center found that after 6 months of following a very low–carbohydrate diet, 96.3% of those with diabetes saw their A1c fall from a median 7.6% to 6.3%. Weight loss was significant, with a median drop of 6.5 kg (14 pounds) for patients with diabetes and 5.7 kg for those with prediabetes. The diet comprises 5%-10% of calories from carbs, but Dr. Glandt does not use numeric targets with her patients.
Blood pressure, triglycerides, and liver enzymes also improved. And though LDL cholesterol went up by 8%, this result may have been offset by an accompanying 13% rise in HDL cholesterol. Of the 78 patients initially on insulin, 62 were able to stop this medication entirely.
Although these results aren’t from a clinical trial, they’re still highly meaningful because the current dietary standard of care for type 2 diabetes can only slow the progression of the disease, not cause remission. Indeed, the idea that type 2 diabetes could be put into remission was not seriously considered by the American Diabetes Association (ADA) until 2009. By 2019, an ADA report concluded that “[r]educing overall carbohydrate intake for individuals with diabetes has demonstrated the most evidence for improving glycemia.” In other words, the best way to improve the key factor in diabetes is to reduce total carbohydrates. Yet, the ADA still advocates filling one quarter of one’s plate with carbohydrate-based foods, an amount that will prevent remission. Given that the ADA’s vision statement is “a life free of diabetes,” it seems negligent not to tell people with a deadly condition that they can reverse this diagnosis.
A 2023 meta-analysis of 42 controlled clinical trials on 4809 patients showed that a very low–carbohydrate ketogenic diet (keto) was “superior” to alternatives for glycemic control. A more recent review of 11 clinical trials found that this diet was equal but not superior to other nutritional approaches in terms of blood sugar control, but this review also concluded that keto led to greater increases in HDL cholesterol and lower triglycerides.
Dr. Glandt’s patients in the Bronx might not seem like obvious low-carb candidates. The diet is considered expensive and difficult to sustain. My interviews with a half dozen patients revealed some of these difficulties, but even for a woman living in a homeless shelter, the obstacles are not insurmountable.
Jerrilyn, who preferred that I use only her first name, lives in a shelter in Queens. While we strolled through a nearby park, she told me about her desire to lose weight and recover from polycystic ovary syndrome, which terrified her because it had caused dramatic hair loss. When she landed in Dr. Glandt’s office at age 28, she weighed 180 pounds.
Less than 5 months later, Jerrilyn had lost 25 pounds, and her period had returned with some regularity. She said she used “food stamps,” known as the Supplemental Nutrition Assistance Program (SNAP), to buy most of her food at local delis because the meals served at the shelter were too heavy in starches. She starts her day with eggs, turkey bacon, and avocado.
“It was hard to give up carbohydrates because in my culture [Latina], we have nothing but carbs: rice, potatoes, yuca,” Jerrilyn shared. She noticed that carbs make her hungrier, but after 3 days of going low-carb, her cravings diminished. “It was like getting over an addiction,” she said.
Jerrilyn told me she’d seen many doctors but none as involved as Dr. Glandt. “It feels awesome to know that I have a lot of really useful information coming from her all the time.” The OwnaHealth app tracks weight, blood pressure, blood sugar, ketones, meals, mood, and cravings. Patients wear continuous glucose monitors and enter other information manually. Ketone bodies are used to measure dietary adherence and are obtained through finger pricks and test strips provided by OwnaHealth. Dr. Glandt gives patients her own food plan, along with free visual guides to low-carbohydrate foods by dietdoctor.com.
Dr. Glandt also sends her patients for regular blood work. She says she does not frequently see a rise in LDL cholesterol, which can sometimes occur on a low-carbohydrate diet. This effect is most common among people who are lean and fit. She says she doesn’t discontinue statins unless cholesterol levels improve significantly.
Samuel Gonzalez, age 56, weighed 275 pounds when he walked into Dr. Glandt’s office this past November. His A1c was 9.2%, but none of his previous doctors had diagnosed him with diabetes. “I was like a walking bag of sugar!” he joked.
A low-carbohydrate diet seemed absurd to a Puerto Rican like himself: “Having coffee without sugar? That’s like sacrilegious in my culture!” exclaimed Mr. Gonzalez. Still, he managed, with SNAP, to cook eggs and bacon for breakfast and some kind of protein for dinner. He keeps lunch light, “like tuna fish,” and finds checking in with the OwnaHealth app to be very helpful. “Every day, I’m on it,” he said. In the past 7 months, he’s lost 50 pounds, normalized his cholesterol and blood pressure levels, and lowered his A1c to 5.5%.
Mr. Gonzalez gets disability payments due to a back injury, and Ms. Efem receives government payments because her husband died serving in the military. Ms. Efem says her new diet challenges her budget, but Mr. Gonzalez says he manages easily.
Mélissa Cruz, a 28-year-old studying to be a nail technician while also doing back office work at a physical therapy practice, says she’s stretched thin. “I end up sad because I can’t put energy into looking up recipes and cooking for me and my boyfriend,” she told me. She’ll often cook rice and plantains for him and meat for herself, but “it’s frustrating when I’m low on funds and can’t figure out what to eat.”
Low-carbohydrate diets have a reputation for being expensive because people often start eating pricier foods, like meat and cheese, to replace cheaper starchy foods such as pasta and rice.
A 2019 cost analysis published in Nutrition & Dietetics compared a low-carbohydrate dietary pattern with the New Zealand government’s recommended guidelines (which are almost identical to those in the United States) and found that it cost only an extra $1.27 in US dollars per person per day. One explanation is that protein and fat are more satiating than carbohydrates, so people who mostly consume these macronutrients often cut back on snacks like packaged chips, crackers, and even fruits. Also, those on a ketogenic diet usually cut down on medications, so the additional $1.27 daily is likely offset by reduced spending at the pharmacy.
It’s not just Bronx residents with low socioeconomic status (SES) who adapt well to low-carbohydrate diets. Among Alabama state employees with diabetes enrolled in a low-carbohydrate dietary program provided by a company called Virta, the low SES population had the best outcomes. Virta also published survey data in 2023 showing that participants in a program with the Veteran’s Administration did not find additional costs to be an obstacle to dietary adherence. In fact, some participants saw cost reductions due to decreased spending on processed snacks and fast foods.
Ms. Cruz told me she struggles financially, yet she’s still lost nearly 30 pounds in 5 months, and her A1c went from 7.1% down to 5.9%, putting her diabetes into remission. Equally motivating for her are the improvements she’s seen in other hormonal issues. Since childhood, she’s had acanthosis, a condition that causes the skin to darken in velvety patches, and more recently, she developed severe hirsutism to the point of growing sideburns. “I had tried going vegan and fasting, but these just weren’t sustainable for me, and I was so overwhelmed with counting calories all the time.” Now, on a low-carbohydrate diet, which doesn’t require calorie counting, she’s finally seeing both these conditions improve significantly.
When I last checked in with Ms. Cruz, she said she had “kind of ghosted” Dr. Glandt due to her work and school constraints, but she hadn’t abandoned the diet. She appreciated, too, that Dr. Glandt had not given up on her and kept calling and messaging. “She’s not at all like a typical doctor who would just tell me to lose weight and shake their head at me,” Ms. Cruz said.
Because Dr. Glandt’s approach is time-intensive and high-touch, it might seem impractical to scale up, but Dr. Glandt’s app uses artificial intelligence to help with communications thus allowing her, with help from part-time health coaches, to care for patients.
This early success in one of the United States’ poorest and sickest neighborhoods should give us hope that type 2 diabetes need not to be a progressive irreversible disease, even among the disadvantaged.
OwnaHealth’s track record, along with that of Virta and other similar low-carbohydrate medical practices also give hope to the food-is-medicine idea. Diabetes can go into remission, and people can be healed, provided that health practitioners prescribe the right foods. And in truth, it’s not a diet. It’s a way of eating that must be maintained. The sustainability of low-carbohydrate diets has been a point of contention, but the Virta trial, with 38% of patients sustaining remission at 2 years, showed that it’s possible. (OwnaHealth, for its part, offers long-term maintenance plans to help patients stay very low-carb permanently.)
Given the tremendous costs and health burden of diabetes, this approach should no doubt be the first line of treatment for doctors and the ADA. The past two decades of clinical trial research have demonstrated that remission of type 2 diabetes is possible through diet alone. It turns out that for metabolic diseases, only certain foods are truly medicine.
Tools and Tips for Clinicians:
- Free two-page keto starter’s guide by OwnaHealth; Dr. Glandt uses this guide with her patients.
- Illustrated low-carb guides by dietdoctor.com
- Free low-carbohydrate starter guide by the Michigan Collaborative for Type 2 Diabetes
- Low-Carb for Any Budget, a free digital booklet by Mark Cucuzzella, MD, and Kristie Sullivan, PhD
- Recipe and meal ideas from Ruled.me, Keto-Mojo.com, and
Dr. Teicholz is the founder of Nutrition Coalition, an independent nonprofit dedicated to ensuring that US dietary guidelines align with current science. She disclosed receiving book royalties from The Big Fat Surprise, and received honorarium not exceeding $2000 for speeches from various sources.
A version of this article appeared on Medscape.com.
For 3 years, Ajala Efem’s type 2 diabetes was so poorly controlled that her blood sugar often soared northward of 500 mg/dL despite insulin shots three to five times a day. She would experience dizziness, vomiting, severe headaches, and the neuropathy in her feet made walking painful. She was also — literally — frothing at the mouth. The 47-year-old single mother of two adult children with mental disabilities feared that she would die.
Ms. Efem lives in the South Bronx, which is among the poorest areas of New York City, where the combined rate of prediabetes and diabetes is close to 30%, the highest rate of any borough in the city.
She had to wait 8 months for an appointment with an endocrinologist, but that visit proved to be life-changing. She lost 28 pounds and got off 15 medications in a single month. She did not join a gym or count calories; she simply changed the food she ate and adopted a low-carb diet.
“I went from being sick to feeling so great,” she told her endocrinologist recently: “My feet aren’t hurting; I’m not in pain; I’m eating as much as I want, and I really enjoy my food so much.”
Ms. Efem’s life-changing visit was with Mariela Glandt, MD, at the offices of Essen Health Care. One month earlier, Dr. Glandt’s company, OwnaHealth, was contracted by Essen to conduct a 100-person pilot program for endocrinology patients. Essen is the largest Medicaid provider in New York City, and “they were desperate for an endocrinologist,” said Dr. Glandt, who trained at Columbia University in New York. So she came — all the way from Madrid, Spain. She commutes monthly, staying for a week each visit.
Dr. Glandt keeps up this punishing schedule because, as she explains, “it’s such a high for me to see these incredible transformations.” Her mostly Black and Hispanic patients are poor and lack resources, yet they lose significant amounts of weight, and their health issues resolve.
“Food is medicine” is an idea very much in vogue. The concept was central to the landmark White House Conference on Hunger, Nutrition, and Health in 2022 and is now the focus of a number of a wide range of government programs. Recently, the Senate held a hearing aimed at further expanding food as medicine programs.
Still, only a single randomized controlled clinical trial has been conducted on this nutritional approach, with unexpectedly disappointing results. In the mid-Atlantic region, 456 food-insecure adults with type 2 diabetes were randomly assigned to usual care or the provision of weekly groceries for their entire families for about 1 year. Provisions for a Mediterranean-style diet included whole grains, fruits and vegetables, lean protein, low-fat dairy products, cereal, brown rice, and bread. In addition, participants received dietary consultations. Yet, those who got free food and coaching did not see improvements in their average blood sugar (the study’s primary outcome), and their low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels appeared to have worsened.
“To be honest, I was surprised,” the study’s lead author, Joseph Doyle, PhD, professor at the Sloan School of Management at MIT in Cambridge, Massachusetts, told me. “I was hoping we would show improved outcomes, but the way to make progress is to do well-randomized trials to find out what works.”
I was not surprised by these results because a recent rigorous systematic review and meta-analysis in The BMJ did not show a Mediterranean-style diet to be the most effective for glycemic control. And Ms. Efem was not in fact following a Mediterranean-style diet.
Ms. Efem’s low-carb success story is anecdotal, but Dr. Glandt has an established track record from her 9 years’ experience as the medical director of the eponymous diabetes center she founded in Tel Aviv. A recent audit of 344 patients from the center found that after 6 months of following a very low–carbohydrate diet, 96.3% of those with diabetes saw their A1c fall from a median 7.6% to 6.3%. Weight loss was significant, with a median drop of 6.5 kg (14 pounds) for patients with diabetes and 5.7 kg for those with prediabetes. The diet comprises 5%-10% of calories from carbs, but Dr. Glandt does not use numeric targets with her patients.
Blood pressure, triglycerides, and liver enzymes also improved. And though LDL cholesterol went up by 8%, this result may have been offset by an accompanying 13% rise in HDL cholesterol. Of the 78 patients initially on insulin, 62 were able to stop this medication entirely.
Although these results aren’t from a clinical trial, they’re still highly meaningful because the current dietary standard of care for type 2 diabetes can only slow the progression of the disease, not cause remission. Indeed, the idea that type 2 diabetes could be put into remission was not seriously considered by the American Diabetes Association (ADA) until 2009. By 2019, an ADA report concluded that “[r]educing overall carbohydrate intake for individuals with diabetes has demonstrated the most evidence for improving glycemia.” In other words, the best way to improve the key factor in diabetes is to reduce total carbohydrates. Yet, the ADA still advocates filling one quarter of one’s plate with carbohydrate-based foods, an amount that will prevent remission. Given that the ADA’s vision statement is “a life free of diabetes,” it seems negligent not to tell people with a deadly condition that they can reverse this diagnosis.
A 2023 meta-analysis of 42 controlled clinical trials on 4809 patients showed that a very low–carbohydrate ketogenic diet (keto) was “superior” to alternatives for glycemic control. A more recent review of 11 clinical trials found that this diet was equal but not superior to other nutritional approaches in terms of blood sugar control, but this review also concluded that keto led to greater increases in HDL cholesterol and lower triglycerides.
Dr. Glandt’s patients in the Bronx might not seem like obvious low-carb candidates. The diet is considered expensive and difficult to sustain. My interviews with a half dozen patients revealed some of these difficulties, but even for a woman living in a homeless shelter, the obstacles are not insurmountable.
Jerrilyn, who preferred that I use only her first name, lives in a shelter in Queens. While we strolled through a nearby park, she told me about her desire to lose weight and recover from polycystic ovary syndrome, which terrified her because it had caused dramatic hair loss. When she landed in Dr. Glandt’s office at age 28, she weighed 180 pounds.
Less than 5 months later, Jerrilyn had lost 25 pounds, and her period had returned with some regularity. She said she used “food stamps,” known as the Supplemental Nutrition Assistance Program (SNAP), to buy most of her food at local delis because the meals served at the shelter were too heavy in starches. She starts her day with eggs, turkey bacon, and avocado.
“It was hard to give up carbohydrates because in my culture [Latina], we have nothing but carbs: rice, potatoes, yuca,” Jerrilyn shared. She noticed that carbs make her hungrier, but after 3 days of going low-carb, her cravings diminished. “It was like getting over an addiction,” she said.
Jerrilyn told me she’d seen many doctors but none as involved as Dr. Glandt. “It feels awesome to know that I have a lot of really useful information coming from her all the time.” The OwnaHealth app tracks weight, blood pressure, blood sugar, ketones, meals, mood, and cravings. Patients wear continuous glucose monitors and enter other information manually. Ketone bodies are used to measure dietary adherence and are obtained through finger pricks and test strips provided by OwnaHealth. Dr. Glandt gives patients her own food plan, along with free visual guides to low-carbohydrate foods by dietdoctor.com.
Dr. Glandt also sends her patients for regular blood work. She says she does not frequently see a rise in LDL cholesterol, which can sometimes occur on a low-carbohydrate diet. This effect is most common among people who are lean and fit. She says she doesn’t discontinue statins unless cholesterol levels improve significantly.
Samuel Gonzalez, age 56, weighed 275 pounds when he walked into Dr. Glandt’s office this past November. His A1c was 9.2%, but none of his previous doctors had diagnosed him with diabetes. “I was like a walking bag of sugar!” he joked.
A low-carbohydrate diet seemed absurd to a Puerto Rican like himself: “Having coffee without sugar? That’s like sacrilegious in my culture!” exclaimed Mr. Gonzalez. Still, he managed, with SNAP, to cook eggs and bacon for breakfast and some kind of protein for dinner. He keeps lunch light, “like tuna fish,” and finds checking in with the OwnaHealth app to be very helpful. “Every day, I’m on it,” he said. In the past 7 months, he’s lost 50 pounds, normalized his cholesterol and blood pressure levels, and lowered his A1c to 5.5%.
Mr. Gonzalez gets disability payments due to a back injury, and Ms. Efem receives government payments because her husband died serving in the military. Ms. Efem says her new diet challenges her budget, but Mr. Gonzalez says he manages easily.
Mélissa Cruz, a 28-year-old studying to be a nail technician while also doing back office work at a physical therapy practice, says she’s stretched thin. “I end up sad because I can’t put energy into looking up recipes and cooking for me and my boyfriend,” she told me. She’ll often cook rice and plantains for him and meat for herself, but “it’s frustrating when I’m low on funds and can’t figure out what to eat.”
Low-carbohydrate diets have a reputation for being expensive because people often start eating pricier foods, like meat and cheese, to replace cheaper starchy foods such as pasta and rice.
A 2019 cost analysis published in Nutrition & Dietetics compared a low-carbohydrate dietary pattern with the New Zealand government’s recommended guidelines (which are almost identical to those in the United States) and found that it cost only an extra $1.27 in US dollars per person per day. One explanation is that protein and fat are more satiating than carbohydrates, so people who mostly consume these macronutrients often cut back on snacks like packaged chips, crackers, and even fruits. Also, those on a ketogenic diet usually cut down on medications, so the additional $1.27 daily is likely offset by reduced spending at the pharmacy.
It’s not just Bronx residents with low socioeconomic status (SES) who adapt well to low-carbohydrate diets. Among Alabama state employees with diabetes enrolled in a low-carbohydrate dietary program provided by a company called Virta, the low SES population had the best outcomes. Virta also published survey data in 2023 showing that participants in a program with the Veteran’s Administration did not find additional costs to be an obstacle to dietary adherence. In fact, some participants saw cost reductions due to decreased spending on processed snacks and fast foods.
Ms. Cruz told me she struggles financially, yet she’s still lost nearly 30 pounds in 5 months, and her A1c went from 7.1% down to 5.9%, putting her diabetes into remission. Equally motivating for her are the improvements she’s seen in other hormonal issues. Since childhood, she’s had acanthosis, a condition that causes the skin to darken in velvety patches, and more recently, she developed severe hirsutism to the point of growing sideburns. “I had tried going vegan and fasting, but these just weren’t sustainable for me, and I was so overwhelmed with counting calories all the time.” Now, on a low-carbohydrate diet, which doesn’t require calorie counting, she’s finally seeing both these conditions improve significantly.
When I last checked in with Ms. Cruz, she said she had “kind of ghosted” Dr. Glandt due to her work and school constraints, but she hadn’t abandoned the diet. She appreciated, too, that Dr. Glandt had not given up on her and kept calling and messaging. “She’s not at all like a typical doctor who would just tell me to lose weight and shake their head at me,” Ms. Cruz said.
Because Dr. Glandt’s approach is time-intensive and high-touch, it might seem impractical to scale up, but Dr. Glandt’s app uses artificial intelligence to help with communications thus allowing her, with help from part-time health coaches, to care for patients.
This early success in one of the United States’ poorest and sickest neighborhoods should give us hope that type 2 diabetes need not to be a progressive irreversible disease, even among the disadvantaged.
OwnaHealth’s track record, along with that of Virta and other similar low-carbohydrate medical practices also give hope to the food-is-medicine idea. Diabetes can go into remission, and people can be healed, provided that health practitioners prescribe the right foods. And in truth, it’s not a diet. It’s a way of eating that must be maintained. The sustainability of low-carbohydrate diets has been a point of contention, but the Virta trial, with 38% of patients sustaining remission at 2 years, showed that it’s possible. (OwnaHealth, for its part, offers long-term maintenance plans to help patients stay very low-carb permanently.)
Given the tremendous costs and health burden of diabetes, this approach should no doubt be the first line of treatment for doctors and the ADA. The past two decades of clinical trial research have demonstrated that remission of type 2 diabetes is possible through diet alone. It turns out that for metabolic diseases, only certain foods are truly medicine.
Tools and Tips for Clinicians:
- Free two-page keto starter’s guide by OwnaHealth; Dr. Glandt uses this guide with her patients.
- Illustrated low-carb guides by dietdoctor.com
- Free low-carbohydrate starter guide by the Michigan Collaborative for Type 2 Diabetes
- Low-Carb for Any Budget, a free digital booklet by Mark Cucuzzella, MD, and Kristie Sullivan, PhD
- Recipe and meal ideas from Ruled.me, Keto-Mojo.com, and
Dr. Teicholz is the founder of Nutrition Coalition, an independent nonprofit dedicated to ensuring that US dietary guidelines align with current science. She disclosed receiving book royalties from The Big Fat Surprise, and received honorarium not exceeding $2000 for speeches from various sources.
A version of this article appeared on Medscape.com.
For 3 years, Ajala Efem’s type 2 diabetes was so poorly controlled that her blood sugar often soared northward of 500 mg/dL despite insulin shots three to five times a day. She would experience dizziness, vomiting, severe headaches, and the neuropathy in her feet made walking painful. She was also — literally — frothing at the mouth. The 47-year-old single mother of two adult children with mental disabilities feared that she would die.
Ms. Efem lives in the South Bronx, which is among the poorest areas of New York City, where the combined rate of prediabetes and diabetes is close to 30%, the highest rate of any borough in the city.
She had to wait 8 months for an appointment with an endocrinologist, but that visit proved to be life-changing. She lost 28 pounds and got off 15 medications in a single month. She did not join a gym or count calories; she simply changed the food she ate and adopted a low-carb diet.
“I went from being sick to feeling so great,” she told her endocrinologist recently: “My feet aren’t hurting; I’m not in pain; I’m eating as much as I want, and I really enjoy my food so much.”
Ms. Efem’s life-changing visit was with Mariela Glandt, MD, at the offices of Essen Health Care. One month earlier, Dr. Glandt’s company, OwnaHealth, was contracted by Essen to conduct a 100-person pilot program for endocrinology patients. Essen is the largest Medicaid provider in New York City, and “they were desperate for an endocrinologist,” said Dr. Glandt, who trained at Columbia University in New York. So she came — all the way from Madrid, Spain. She commutes monthly, staying for a week each visit.
Dr. Glandt keeps up this punishing schedule because, as she explains, “it’s such a high for me to see these incredible transformations.” Her mostly Black and Hispanic patients are poor and lack resources, yet they lose significant amounts of weight, and their health issues resolve.
“Food is medicine” is an idea very much in vogue. The concept was central to the landmark White House Conference on Hunger, Nutrition, and Health in 2022 and is now the focus of a number of a wide range of government programs. Recently, the Senate held a hearing aimed at further expanding food as medicine programs.
Still, only a single randomized controlled clinical trial has been conducted on this nutritional approach, with unexpectedly disappointing results. In the mid-Atlantic region, 456 food-insecure adults with type 2 diabetes were randomly assigned to usual care or the provision of weekly groceries for their entire families for about 1 year. Provisions for a Mediterranean-style diet included whole grains, fruits and vegetables, lean protein, low-fat dairy products, cereal, brown rice, and bread. In addition, participants received dietary consultations. Yet, those who got free food and coaching did not see improvements in their average blood sugar (the study’s primary outcome), and their low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels appeared to have worsened.
“To be honest, I was surprised,” the study’s lead author, Joseph Doyle, PhD, professor at the Sloan School of Management at MIT in Cambridge, Massachusetts, told me. “I was hoping we would show improved outcomes, but the way to make progress is to do well-randomized trials to find out what works.”
I was not surprised by these results because a recent rigorous systematic review and meta-analysis in The BMJ did not show a Mediterranean-style diet to be the most effective for glycemic control. And Ms. Efem was not in fact following a Mediterranean-style diet.
Ms. Efem’s low-carb success story is anecdotal, but Dr. Glandt has an established track record from her 9 years’ experience as the medical director of the eponymous diabetes center she founded in Tel Aviv. A recent audit of 344 patients from the center found that after 6 months of following a very low–carbohydrate diet, 96.3% of those with diabetes saw their A1c fall from a median 7.6% to 6.3%. Weight loss was significant, with a median drop of 6.5 kg (14 pounds) for patients with diabetes and 5.7 kg for those with prediabetes. The diet comprises 5%-10% of calories from carbs, but Dr. Glandt does not use numeric targets with her patients.
Blood pressure, triglycerides, and liver enzymes also improved. And though LDL cholesterol went up by 8%, this result may have been offset by an accompanying 13% rise in HDL cholesterol. Of the 78 patients initially on insulin, 62 were able to stop this medication entirely.
Although these results aren’t from a clinical trial, they’re still highly meaningful because the current dietary standard of care for type 2 diabetes can only slow the progression of the disease, not cause remission. Indeed, the idea that type 2 diabetes could be put into remission was not seriously considered by the American Diabetes Association (ADA) until 2009. By 2019, an ADA report concluded that “[r]educing overall carbohydrate intake for individuals with diabetes has demonstrated the most evidence for improving glycemia.” In other words, the best way to improve the key factor in diabetes is to reduce total carbohydrates. Yet, the ADA still advocates filling one quarter of one’s plate with carbohydrate-based foods, an amount that will prevent remission. Given that the ADA’s vision statement is “a life free of diabetes,” it seems negligent not to tell people with a deadly condition that they can reverse this diagnosis.
A 2023 meta-analysis of 42 controlled clinical trials on 4809 patients showed that a very low–carbohydrate ketogenic diet (keto) was “superior” to alternatives for glycemic control. A more recent review of 11 clinical trials found that this diet was equal but not superior to other nutritional approaches in terms of blood sugar control, but this review also concluded that keto led to greater increases in HDL cholesterol and lower triglycerides.
Dr. Glandt’s patients in the Bronx might not seem like obvious low-carb candidates. The diet is considered expensive and difficult to sustain. My interviews with a half dozen patients revealed some of these difficulties, but even for a woman living in a homeless shelter, the obstacles are not insurmountable.
Jerrilyn, who preferred that I use only her first name, lives in a shelter in Queens. While we strolled through a nearby park, she told me about her desire to lose weight and recover from polycystic ovary syndrome, which terrified her because it had caused dramatic hair loss. When she landed in Dr. Glandt’s office at age 28, she weighed 180 pounds.
Less than 5 months later, Jerrilyn had lost 25 pounds, and her period had returned with some regularity. She said she used “food stamps,” known as the Supplemental Nutrition Assistance Program (SNAP), to buy most of her food at local delis because the meals served at the shelter were too heavy in starches. She starts her day with eggs, turkey bacon, and avocado.
“It was hard to give up carbohydrates because in my culture [Latina], we have nothing but carbs: rice, potatoes, yuca,” Jerrilyn shared. She noticed that carbs make her hungrier, but after 3 days of going low-carb, her cravings diminished. “It was like getting over an addiction,” she said.
Jerrilyn told me she’d seen many doctors but none as involved as Dr. Glandt. “It feels awesome to know that I have a lot of really useful information coming from her all the time.” The OwnaHealth app tracks weight, blood pressure, blood sugar, ketones, meals, mood, and cravings. Patients wear continuous glucose monitors and enter other information manually. Ketone bodies are used to measure dietary adherence and are obtained through finger pricks and test strips provided by OwnaHealth. Dr. Glandt gives patients her own food plan, along with free visual guides to low-carbohydrate foods by dietdoctor.com.
Dr. Glandt also sends her patients for regular blood work. She says she does not frequently see a rise in LDL cholesterol, which can sometimes occur on a low-carbohydrate diet. This effect is most common among people who are lean and fit. She says she doesn’t discontinue statins unless cholesterol levels improve significantly.
Samuel Gonzalez, age 56, weighed 275 pounds when he walked into Dr. Glandt’s office this past November. His A1c was 9.2%, but none of his previous doctors had diagnosed him with diabetes. “I was like a walking bag of sugar!” he joked.
A low-carbohydrate diet seemed absurd to a Puerto Rican like himself: “Having coffee without sugar? That’s like sacrilegious in my culture!” exclaimed Mr. Gonzalez. Still, he managed, with SNAP, to cook eggs and bacon for breakfast and some kind of protein for dinner. He keeps lunch light, “like tuna fish,” and finds checking in with the OwnaHealth app to be very helpful. “Every day, I’m on it,” he said. In the past 7 months, he’s lost 50 pounds, normalized his cholesterol and blood pressure levels, and lowered his A1c to 5.5%.
Mr. Gonzalez gets disability payments due to a back injury, and Ms. Efem receives government payments because her husband died serving in the military. Ms. Efem says her new diet challenges her budget, but Mr. Gonzalez says he manages easily.
Mélissa Cruz, a 28-year-old studying to be a nail technician while also doing back office work at a physical therapy practice, says she’s stretched thin. “I end up sad because I can’t put energy into looking up recipes and cooking for me and my boyfriend,” she told me. She’ll often cook rice and plantains for him and meat for herself, but “it’s frustrating when I’m low on funds and can’t figure out what to eat.”
Low-carbohydrate diets have a reputation for being expensive because people often start eating pricier foods, like meat and cheese, to replace cheaper starchy foods such as pasta and rice.
A 2019 cost analysis published in Nutrition & Dietetics compared a low-carbohydrate dietary pattern with the New Zealand government’s recommended guidelines (which are almost identical to those in the United States) and found that it cost only an extra $1.27 in US dollars per person per day. One explanation is that protein and fat are more satiating than carbohydrates, so people who mostly consume these macronutrients often cut back on snacks like packaged chips, crackers, and even fruits. Also, those on a ketogenic diet usually cut down on medications, so the additional $1.27 daily is likely offset by reduced spending at the pharmacy.
It’s not just Bronx residents with low socioeconomic status (SES) who adapt well to low-carbohydrate diets. Among Alabama state employees with diabetes enrolled in a low-carbohydrate dietary program provided by a company called Virta, the low SES population had the best outcomes. Virta also published survey data in 2023 showing that participants in a program with the Veteran’s Administration did not find additional costs to be an obstacle to dietary adherence. In fact, some participants saw cost reductions due to decreased spending on processed snacks and fast foods.
Ms. Cruz told me she struggles financially, yet she’s still lost nearly 30 pounds in 5 months, and her A1c went from 7.1% down to 5.9%, putting her diabetes into remission. Equally motivating for her are the improvements she’s seen in other hormonal issues. Since childhood, she’s had acanthosis, a condition that causes the skin to darken in velvety patches, and more recently, she developed severe hirsutism to the point of growing sideburns. “I had tried going vegan and fasting, but these just weren’t sustainable for me, and I was so overwhelmed with counting calories all the time.” Now, on a low-carbohydrate diet, which doesn’t require calorie counting, she’s finally seeing both these conditions improve significantly.
When I last checked in with Ms. Cruz, she said she had “kind of ghosted” Dr. Glandt due to her work and school constraints, but she hadn’t abandoned the diet. She appreciated, too, that Dr. Glandt had not given up on her and kept calling and messaging. “She’s not at all like a typical doctor who would just tell me to lose weight and shake their head at me,” Ms. Cruz said.
Because Dr. Glandt’s approach is time-intensive and high-touch, it might seem impractical to scale up, but Dr. Glandt’s app uses artificial intelligence to help with communications thus allowing her, with help from part-time health coaches, to care for patients.
This early success in one of the United States’ poorest and sickest neighborhoods should give us hope that type 2 diabetes need not to be a progressive irreversible disease, even among the disadvantaged.
OwnaHealth’s track record, along with that of Virta and other similar low-carbohydrate medical practices also give hope to the food-is-medicine idea. Diabetes can go into remission, and people can be healed, provided that health practitioners prescribe the right foods. And in truth, it’s not a diet. It’s a way of eating that must be maintained. The sustainability of low-carbohydrate diets has been a point of contention, but the Virta trial, with 38% of patients sustaining remission at 2 years, showed that it’s possible. (OwnaHealth, for its part, offers long-term maintenance plans to help patients stay very low-carb permanently.)
Given the tremendous costs and health burden of diabetes, this approach should no doubt be the first line of treatment for doctors and the ADA. The past two decades of clinical trial research have demonstrated that remission of type 2 diabetes is possible through diet alone. It turns out that for metabolic diseases, only certain foods are truly medicine.
Tools and Tips for Clinicians:
- Free two-page keto starter’s guide by OwnaHealth; Dr. Glandt uses this guide with her patients.
- Illustrated low-carb guides by dietdoctor.com
- Free low-carbohydrate starter guide by the Michigan Collaborative for Type 2 Diabetes
- Low-Carb for Any Budget, a free digital booklet by Mark Cucuzzella, MD, and Kristie Sullivan, PhD
- Recipe and meal ideas from Ruled.me, Keto-Mojo.com, and
Dr. Teicholz is the founder of Nutrition Coalition, an independent nonprofit dedicated to ensuring that US dietary guidelines align with current science. She disclosed receiving book royalties from The Big Fat Surprise, and received honorarium not exceeding $2000 for speeches from various sources.
A version of this article appeared on Medscape.com.
In Some Patients, Antiseizure Medications Can Cause Severe Skin Reactions
according to authors of a recent review. And if putting higher-risk patients on drugs most associated with human leukocyte antigen (HLA)–related reaction risk before test results are available, authors advised starting at low doses and titrating slowly.
“When someone is having a seizure drug prescribed,” said senior author Ram Mani, MD, MSCE, chief of epilepsy at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, “it’s often a tense clinical situation because the patient has either had the first few seizures of their life, or they’ve had a worsening in their seizures.”
To help physicians optimize choices, Dr. Mani and colleagues reviewed literature regarding 31 ASMs. Their study was published in Current Treatment Options in Neurology.
Overall, said Dr. Mani, incidence of benign skin reactions such as morbilliform exanthematous eruptions, which account for 95% of cutaneous adverse drug reactions (CADRs), ranges from a few percent up to 15%. “It’s a somewhat common occurrence. Fortunately, the reactions that can lead to morbidity and mortality are fairly rare.”
Severe Cutaneous Adverse Reactions
Among the five ASMs approved by the Food and Drug Administration since 2018, cenobamate has sparked the greatest concern. In early clinical development for epilepsy, a fast titration schedule (starting at 50 mg/day and increasing by 50 mg every 2 weeks to at least 200 mg/day) resulted in three cases of drug reaction with eosinophilia and systemic symptoms (DRESS, also called drug-induced hypersensitivity reaction/DIHS), including one fatal case. Based on a phase 3 trial, the drug’s manufacturer now recommends starting at 12.5 mg and titrating more slowly.
DRESS/DIHS appears within 2-6 weeks of drug exposure. Along with malaise, fever, and conjunctivitis, symptoms can include skin eruptions ranging from morbilliform to hemorrhagic and bullous. “Facial edema and early facial rash are classic findings,” the authors added. DRESS also can involve painful lymphadenopathy and potentially life-threatening damage to the liver, heart, and other organs.
Stevens-Johnson syndrome (SJS), which is characterized by detached skin measuring less than 10% of the entire body surface area, typically happens within the first month of drug exposure. Flu-like symptoms can appear 1-3 days before erythematous to dusky macules, commonly on the chest, as well as cutaneous and mucosal erosions. Along with the skin and conjunctiva, SJS can affect the eyes, lungs, liver, bone marrow, and gastrointestinal tract.
When patients present with possible DRESS or SJS, the authors recommended inpatient multidisciplinary care. Having ready access to blood tests can help assess severity and prognosis, Dr. Mani explained. Inpatient evaluation and treatment also may allow faster access to other specialists as needed, and monitoring of potential seizure exacerbation in patients with uncontrolled seizures for whom the drug provided benefit but required abrupt discontinuation.
Often, he added, all hope is not lost for future use of the medication after a minor skin reaction. A case series and literature review of mild lamotrigine-associated CADRs showed that most patients could reintroduce and titrate lamotrigine by waiting at least 4 weeks, beginning at 5 mg/day, and gradually increasing to 25 mg/day.
Identifying Those at Risk
With millions of patients being newly prescribed ASMs annually, accurately screening out all people at risk of severe cutaneous adverse reactions based on available genetic information is impossible. The complexity of evolving recommendations for HLA testing makes them hard to remember, Dr. Mani said. “Development and better use of clinical decision support systems can help.”
Accordingly, he starts with a thorough history and physical examination, inquiring about prior skin reactions or hypersensitivity, which are risk factors for future reactions to drugs such as carbamazepine, phenytoin, phenobarbital, oxcarbazepine, lamotrigine, rufinamide, and zonisamide. “Most of the medicines that the HLA tests are being done for are not the initial medicines I typically prescribe for a patient with newly diagnosed epilepsy,” said Dr. Mani. For ASM-naive patients with moderate or high risk of skin hypersensitivity reactions, he usually starts with lacosamide, levetiracetam, or brivaracetam. Additional low-risk drugs he considers in more complex cases include valproate, topiramate, and clobazam.
Only if a patient’s initial ASM causes problems will Dr. Mani consider higher-risk options and order HLA tests for patients belonging to indicated groups — such as testing for HLA-B*15:02 in Asian patients being considered for carbamazepine. About once weekly, he must put a patient on a potentially higher-risk drug before test results are available. If after a thorough risk-benefit discussion, he and the patient agree that the higher-risk drug is warranted, Dr. Mani starts at a lower-than-labeled dose, with a slower titration schedule that typically extends the ramp-up period by 1 week.
Fortunately, Dr. Mani said that, in 20 years of practice, he has seen more misdiagnoses — involving rashes from poison ivy, viral infections, or allergies — than actual ASM-induced reactions. “That’s why the patient, family, and practitioner need to be open-minded about what could be causing the rash.”
Dr. Mani reported no relevant conflicts. The study authors reported no funding sources.
according to authors of a recent review. And if putting higher-risk patients on drugs most associated with human leukocyte antigen (HLA)–related reaction risk before test results are available, authors advised starting at low doses and titrating slowly.
“When someone is having a seizure drug prescribed,” said senior author Ram Mani, MD, MSCE, chief of epilepsy at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, “it’s often a tense clinical situation because the patient has either had the first few seizures of their life, or they’ve had a worsening in their seizures.”
To help physicians optimize choices, Dr. Mani and colleagues reviewed literature regarding 31 ASMs. Their study was published in Current Treatment Options in Neurology.
Overall, said Dr. Mani, incidence of benign skin reactions such as morbilliform exanthematous eruptions, which account for 95% of cutaneous adverse drug reactions (CADRs), ranges from a few percent up to 15%. “It’s a somewhat common occurrence. Fortunately, the reactions that can lead to morbidity and mortality are fairly rare.”
Severe Cutaneous Adverse Reactions
Among the five ASMs approved by the Food and Drug Administration since 2018, cenobamate has sparked the greatest concern. In early clinical development for epilepsy, a fast titration schedule (starting at 50 mg/day and increasing by 50 mg every 2 weeks to at least 200 mg/day) resulted in three cases of drug reaction with eosinophilia and systemic symptoms (DRESS, also called drug-induced hypersensitivity reaction/DIHS), including one fatal case. Based on a phase 3 trial, the drug’s manufacturer now recommends starting at 12.5 mg and titrating more slowly.
DRESS/DIHS appears within 2-6 weeks of drug exposure. Along with malaise, fever, and conjunctivitis, symptoms can include skin eruptions ranging from morbilliform to hemorrhagic and bullous. “Facial edema and early facial rash are classic findings,” the authors added. DRESS also can involve painful lymphadenopathy and potentially life-threatening damage to the liver, heart, and other organs.
Stevens-Johnson syndrome (SJS), which is characterized by detached skin measuring less than 10% of the entire body surface area, typically happens within the first month of drug exposure. Flu-like symptoms can appear 1-3 days before erythematous to dusky macules, commonly on the chest, as well as cutaneous and mucosal erosions. Along with the skin and conjunctiva, SJS can affect the eyes, lungs, liver, bone marrow, and gastrointestinal tract.
When patients present with possible DRESS or SJS, the authors recommended inpatient multidisciplinary care. Having ready access to blood tests can help assess severity and prognosis, Dr. Mani explained. Inpatient evaluation and treatment also may allow faster access to other specialists as needed, and monitoring of potential seizure exacerbation in patients with uncontrolled seizures for whom the drug provided benefit but required abrupt discontinuation.
Often, he added, all hope is not lost for future use of the medication after a minor skin reaction. A case series and literature review of mild lamotrigine-associated CADRs showed that most patients could reintroduce and titrate lamotrigine by waiting at least 4 weeks, beginning at 5 mg/day, and gradually increasing to 25 mg/day.
Identifying Those at Risk
With millions of patients being newly prescribed ASMs annually, accurately screening out all people at risk of severe cutaneous adverse reactions based on available genetic information is impossible. The complexity of evolving recommendations for HLA testing makes them hard to remember, Dr. Mani said. “Development and better use of clinical decision support systems can help.”
Accordingly, he starts with a thorough history and physical examination, inquiring about prior skin reactions or hypersensitivity, which are risk factors for future reactions to drugs such as carbamazepine, phenytoin, phenobarbital, oxcarbazepine, lamotrigine, rufinamide, and zonisamide. “Most of the medicines that the HLA tests are being done for are not the initial medicines I typically prescribe for a patient with newly diagnosed epilepsy,” said Dr. Mani. For ASM-naive patients with moderate or high risk of skin hypersensitivity reactions, he usually starts with lacosamide, levetiracetam, or brivaracetam. Additional low-risk drugs he considers in more complex cases include valproate, topiramate, and clobazam.
Only if a patient’s initial ASM causes problems will Dr. Mani consider higher-risk options and order HLA tests for patients belonging to indicated groups — such as testing for HLA-B*15:02 in Asian patients being considered for carbamazepine. About once weekly, he must put a patient on a potentially higher-risk drug before test results are available. If after a thorough risk-benefit discussion, he and the patient agree that the higher-risk drug is warranted, Dr. Mani starts at a lower-than-labeled dose, with a slower titration schedule that typically extends the ramp-up period by 1 week.
Fortunately, Dr. Mani said that, in 20 years of practice, he has seen more misdiagnoses — involving rashes from poison ivy, viral infections, or allergies — than actual ASM-induced reactions. “That’s why the patient, family, and practitioner need to be open-minded about what could be causing the rash.”
Dr. Mani reported no relevant conflicts. The study authors reported no funding sources.
according to authors of a recent review. And if putting higher-risk patients on drugs most associated with human leukocyte antigen (HLA)–related reaction risk before test results are available, authors advised starting at low doses and titrating slowly.
“When someone is having a seizure drug prescribed,” said senior author Ram Mani, MD, MSCE, chief of epilepsy at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, “it’s often a tense clinical situation because the patient has either had the first few seizures of their life, or they’ve had a worsening in their seizures.”
To help physicians optimize choices, Dr. Mani and colleagues reviewed literature regarding 31 ASMs. Their study was published in Current Treatment Options in Neurology.
Overall, said Dr. Mani, incidence of benign skin reactions such as morbilliform exanthematous eruptions, which account for 95% of cutaneous adverse drug reactions (CADRs), ranges from a few percent up to 15%. “It’s a somewhat common occurrence. Fortunately, the reactions that can lead to morbidity and mortality are fairly rare.”
Severe Cutaneous Adverse Reactions
Among the five ASMs approved by the Food and Drug Administration since 2018, cenobamate has sparked the greatest concern. In early clinical development for epilepsy, a fast titration schedule (starting at 50 mg/day and increasing by 50 mg every 2 weeks to at least 200 mg/day) resulted in three cases of drug reaction with eosinophilia and systemic symptoms (DRESS, also called drug-induced hypersensitivity reaction/DIHS), including one fatal case. Based on a phase 3 trial, the drug’s manufacturer now recommends starting at 12.5 mg and titrating more slowly.
DRESS/DIHS appears within 2-6 weeks of drug exposure. Along with malaise, fever, and conjunctivitis, symptoms can include skin eruptions ranging from morbilliform to hemorrhagic and bullous. “Facial edema and early facial rash are classic findings,” the authors added. DRESS also can involve painful lymphadenopathy and potentially life-threatening damage to the liver, heart, and other organs.
Stevens-Johnson syndrome (SJS), which is characterized by detached skin measuring less than 10% of the entire body surface area, typically happens within the first month of drug exposure. Flu-like symptoms can appear 1-3 days before erythematous to dusky macules, commonly on the chest, as well as cutaneous and mucosal erosions. Along with the skin and conjunctiva, SJS can affect the eyes, lungs, liver, bone marrow, and gastrointestinal tract.
When patients present with possible DRESS or SJS, the authors recommended inpatient multidisciplinary care. Having ready access to blood tests can help assess severity and prognosis, Dr. Mani explained. Inpatient evaluation and treatment also may allow faster access to other specialists as needed, and monitoring of potential seizure exacerbation in patients with uncontrolled seizures for whom the drug provided benefit but required abrupt discontinuation.
Often, he added, all hope is not lost for future use of the medication after a minor skin reaction. A case series and literature review of mild lamotrigine-associated CADRs showed that most patients could reintroduce and titrate lamotrigine by waiting at least 4 weeks, beginning at 5 mg/day, and gradually increasing to 25 mg/day.
Identifying Those at Risk
With millions of patients being newly prescribed ASMs annually, accurately screening out all people at risk of severe cutaneous adverse reactions based on available genetic information is impossible. The complexity of evolving recommendations for HLA testing makes them hard to remember, Dr. Mani said. “Development and better use of clinical decision support systems can help.”
Accordingly, he starts with a thorough history and physical examination, inquiring about prior skin reactions or hypersensitivity, which are risk factors for future reactions to drugs such as carbamazepine, phenytoin, phenobarbital, oxcarbazepine, lamotrigine, rufinamide, and zonisamide. “Most of the medicines that the HLA tests are being done for are not the initial medicines I typically prescribe for a patient with newly diagnosed epilepsy,” said Dr. Mani. For ASM-naive patients with moderate or high risk of skin hypersensitivity reactions, he usually starts with lacosamide, levetiracetam, or brivaracetam. Additional low-risk drugs he considers in more complex cases include valproate, topiramate, and clobazam.
Only if a patient’s initial ASM causes problems will Dr. Mani consider higher-risk options and order HLA tests for patients belonging to indicated groups — such as testing for HLA-B*15:02 in Asian patients being considered for carbamazepine. About once weekly, he must put a patient on a potentially higher-risk drug before test results are available. If after a thorough risk-benefit discussion, he and the patient agree that the higher-risk drug is warranted, Dr. Mani starts at a lower-than-labeled dose, with a slower titration schedule that typically extends the ramp-up period by 1 week.
Fortunately, Dr. Mani said that, in 20 years of practice, he has seen more misdiagnoses — involving rashes from poison ivy, viral infections, or allergies — than actual ASM-induced reactions. “That’s why the patient, family, and practitioner need to be open-minded about what could be causing the rash.”
Dr. Mani reported no relevant conflicts. The study authors reported no funding sources.
FROM CURRENT TREATMENT OPTIONS IN NEUROLOGY