Pustular psoriasis of pregnancy (PPP) is a rare but potentially serious dermatosis of pregnancy. Left untreated, PPP can be fatal for both the mother and the fetus.^1,2 Contrary to many other pregnancy dermatoses, which are typically limited to the skin, systemic signs and symptoms often accompany PPP, including fatigue, fever, diarrhea, delirium, elevated markers of inflammation such as an increased erythrocyte sedimentation rate, and increased white blood cell counts.^1,3,4 Progression of the rash to erythroderma with subsequent dangerous fluid and electrolyte imbalances, loss of thermoregulation in the skin, and the risk for secondary infection and sepsis can occur in severe cases.^1,5 

Increasing evidence suggests that PPP is likely a variant of generalized pustular psoriasis (GPP), which can be vulnerable to a variety of triggers, including metabolic disturbances, systemic steroid withdrawals, and pregnancy; however, classification of the disease as either a variant of disease or a distinct disease state remains controversial.^1,6 Early recognition and prompt treatment are critically important given the potential for fetal and maternal morbidity and mortality that is associated with PPP.^1,6,7 

Clinical Presentation

Most cases of PPP involve presentation in the early part of the third trimester of pregnancy; postpartum PPP has been reported but is exceedingly rare.¹ Typically, lesions develop in the skin folds and spread centrifugally.^2,6 The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet usually are spared; occasionally, involvement of oral and esophageal mucosae is seen. Biopsy findings usually comprise spongiform pustules with neutrophil invasion into the epidermis. Characteristic laboratory findings include electrolyte derangements with elevated erythrocyte sedimentation rate and leukocytosis.^2,8 

As was seen in the case presentation, PPP largely resolves following childbirth; however, there is a significant risk for recurrence in subsequent pregnancies, which may be more severe and present earlier.^1,6 Menstrual cycle changes and the use of oral contraceptives, particularly those containing progesterone, also have been associated with PPP flares.^1,6 Although its pathophysiology is not entirely understood, the development of PPP is believed to be associated with the hormonal changes that occur in the third trimester, in particular elevated progesterone levels.⁶ 

Treatment

Oral corticosteroids remain the mainstay of treatment for PPP.⁶ Lower dosages ranging from 15 to 30 mg daily can be used for mild cases.¹ More severe cases usually are treated with an initial trial of prednisone or prednisolone with dosages ranging from 30 mg daily to as high as 60 to 80 mg daily. Higher doses should be used with caution, however, as they may result in reduced fetal reactivity on fetal monitoring.^1,9 Treatment at least throughout the remainder of a patient’s pregnancy usually is required, with subsequent gradual tapering of the medication.¹ 
 

Although it was once reserved for severe or refractory PPP, in 2012, a task force from the National Psoriasis Foundation categorized cyclosporine as an appropriate first-line therapy for PPP.¹⁰ Published case reports have documented the successful treatment of PPP with cyclosporine in cases that did not respond to systemic steroids.^6,11 

Several case reports have documented the safe use of anti–tumor necrosis factors (TNFs), primarily infliximab, for PPP.¹² Infliximab and other TNF-α antibodies are pregnancy category B, but limited controlled human data exist regarding their safety in pregnancy.¹

Finally, the addition of narrowband UVB light therapy to oral corticosteroids also has been proposed as a safe treatment of refractory disease.^6,13 Unlike psoralen plus UVA, which is usually reserved for postpartum use, narrowband UVB light therapy has been shown to be safe for use during pregnancy.¹ 

Future Directions

Genetic and pathogenesis studies have described involvement of IL-1 and IL-36 cytokines in GPP.¹ These interleukins are important in neutrophil chemotaxis leading to pustule formation.  In addition, as in other psoriasis variants, TNF-α and IL-17α are important. Such findings may help to pave the way for the development of future therapies for both GPP and PPP. 
 

Bottom Line

Clinicians should have a high index of suspicion for PPP in pregnant women who present with widespread cutaneous eruptions. Presently, oral corticosteroids paired with close involvement of obstetric care remains the cornerstone of treatment for PPP. As the case report illustrates, effective diagnosis, treatment, and monitoring are essential for safe outcomes for both mother and baby.
 

Pustular psoriasis of pregnancy (PPP) is a rare but potentially serious dermatosis of pregnancy. Left untreated, PPP can be fatal for both the mother and the fetus.^1,2 Contrary to many other pregnancy dermatoses, which are typically limited to the skin, systemic signs and symptoms often accompany PPP, including fatigue, fever, diarrhea, delirium, elevated markers of inflammation such as an increased erythrocyte sedimentation rate, and increased white blood cell counts.^1,3,4 Progression of the rash to erythroderma with subsequent dangerous fluid and electrolyte imbalances, loss of thermoregulation in the skin, and the risk for secondary infection and sepsis can occur in severe cases.^1,5 

Increasing evidence suggests that PPP is likely a variant of generalized pustular psoriasis (GPP), which can be vulnerable to a variety of triggers, including metabolic disturbances, systemic steroid withdrawals, and pregnancy; however, classification of the disease as either a variant of disease or a distinct disease state remains controversial.^1,6 Early recognition and prompt treatment are critically important given the potential for fetal and maternal morbidity and mortality that is associated with PPP.^1,6,7 

Clinical Presentation

Most cases of PPP involve presentation in the early part of the third trimester of pregnancy; postpartum PPP has been reported but is exceedingly rare.¹ Typically, lesions develop in the skin folds and spread centrifugally.^2,6 The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet usually are spared; occasionally, involvement of oral and esophageal mucosae is seen. Biopsy findings usually comprise spongiform pustules with neutrophil invasion into the epidermis. Characteristic laboratory findings include electrolyte derangements with elevated erythrocyte sedimentation rate and leukocytosis.^2,8 

As was seen in the case presentation, PPP largely resolves following childbirth; however, there is a significant risk for recurrence in subsequent pregnancies, which may be more severe and present earlier.^1,6 Menstrual cycle changes and the use of oral contraceptives, particularly those containing progesterone, also have been associated with PPP flares.^1,6 Although its pathophysiology is not entirely understood, the development of PPP is believed to be associated with the hormonal changes that occur in the third trimester, in particular elevated progesterone levels.⁶ 

Treatment

Oral corticosteroids remain the mainstay of treatment for PPP.⁶ Lower dosages ranging from 15 to 30 mg daily can be used for mild cases.¹ More severe cases usually are treated with an initial trial of prednisone or prednisolone with dosages ranging from 30 mg daily to as high as 60 to 80 mg daily. Higher doses should be used with caution, however, as they may result in reduced fetal reactivity on fetal monitoring.^1,9 Treatment at least throughout the remainder of a patient’s pregnancy usually is required, with subsequent gradual tapering of the medication.¹ 
 

Although it was once reserved for severe or refractory PPP, in 2012, a task force from the National Psoriasis Foundation categorized cyclosporine as an appropriate first-line therapy for PPP.¹⁰ Published case reports have documented the successful treatment of PPP with cyclosporine in cases that did not respond to systemic steroids.^6,11 

Several case reports have documented the safe use of anti–tumor necrosis factors (TNFs), primarily infliximab, for PPP.¹² Infliximab and other TNF-α antibodies are pregnancy category B, but limited controlled human data exist regarding their safety in pregnancy.¹

Finally, the addition of narrowband UVB light therapy to oral corticosteroids also has been proposed as a safe treatment of refractory disease.^6,13 Unlike psoralen plus UVA, which is usually reserved for postpartum use, narrowband UVB light therapy has been shown to be safe for use during pregnancy.¹ 

Future Directions

Genetic and pathogenesis studies have described involvement of IL-1 and IL-36 cytokines in GPP.¹ These interleukins are important in neutrophil chemotaxis leading to pustule formation.  In addition, as in other psoriasis variants, TNF-α and IL-17α are important. Such findings may help to pave the way for the development of future therapies for both GPP and PPP. 
 

Bottom Line

Clinicians should have a high index of suspicion for PPP in pregnant women who present with widespread cutaneous eruptions. Presently, oral corticosteroids paired with close involvement of obstetric care remains the cornerstone of treatment for PPP. As the case report illustrates, effective diagnosis, treatment, and monitoring are essential for safe outcomes for both mother and baby.
 

Pustular psoriasis of pregnancy (PPP) is a rare but potentially serious dermatosis of pregnancy. Left untreated, PPP can be fatal for both the mother and the fetus.^1,2 Contrary to many other pregnancy dermatoses, which are typically limited to the skin, systemic signs and symptoms often accompany PPP, including fatigue, fever, diarrhea, delirium, elevated markers of inflammation such as an increased erythrocyte sedimentation rate, and increased white blood cell counts.^1,3,4 Progression of the rash to erythroderma with subsequent dangerous fluid and electrolyte imbalances, loss of thermoregulation in the skin, and the risk for secondary infection and sepsis can occur in severe cases.^1,5 

Increasing evidence suggests that PPP is likely a variant of generalized pustular psoriasis (GPP), which can be vulnerable to a variety of triggers, including metabolic disturbances, systemic steroid withdrawals, and pregnancy; however, classification of the disease as either a variant of disease or a distinct disease state remains controversial.^1,6 Early recognition and prompt treatment are critically important given the potential for fetal and maternal morbidity and mortality that is associated with PPP.^1,6,7 

Clinical Presentation

Most cases of PPP involve presentation in the early part of the third trimester of pregnancy; postpartum PPP has been reported but is exceedingly rare.¹ Typically, lesions develop in the skin folds and spread centrifugally.^2,6 The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet usually are spared; occasionally, involvement of oral and esophageal mucosae is seen. Biopsy findings usually comprise spongiform pustules with neutrophil invasion into the epidermis. Characteristic laboratory findings include electrolyte derangements with elevated erythrocyte sedimentation rate and leukocytosis.^2,8 

As was seen in the case presentation, PPP largely resolves following childbirth; however, there is a significant risk for recurrence in subsequent pregnancies, which may be more severe and present earlier.^1,6 Menstrual cycle changes and the use of oral contraceptives, particularly those containing progesterone, also have been associated with PPP flares.^1,6 Although its pathophysiology is not entirely understood, the development of PPP is believed to be associated with the hormonal changes that occur in the third trimester, in particular elevated progesterone levels.⁶ 

Treatment

Oral corticosteroids remain the mainstay of treatment for PPP.⁶ Lower dosages ranging from 15 to 30 mg daily can be used for mild cases.¹ More severe cases usually are treated with an initial trial of prednisone or prednisolone with dosages ranging from 30 mg daily to as high as 60 to 80 mg daily. Higher doses should be used with caution, however, as they may result in reduced fetal reactivity on fetal monitoring.^1,9 Treatment at least throughout the remainder of a patient’s pregnancy usually is required, with subsequent gradual tapering of the medication.¹ 
 

Although it was once reserved for severe or refractory PPP, in 2012, a task force from the National Psoriasis Foundation categorized cyclosporine as an appropriate first-line therapy for PPP.¹⁰ Published case reports have documented the successful treatment of PPP with cyclosporine in cases that did not respond to systemic steroids.^6,11 

Several case reports have documented the safe use of anti–tumor necrosis factors (TNFs), primarily infliximab, for PPP.¹² Infliximab and other TNF-α antibodies are pregnancy category B, but limited controlled human data exist regarding their safety in pregnancy.¹

Finally, the addition of narrowband UVB light therapy to oral corticosteroids also has been proposed as a safe treatment of refractory disease.^6,13 Unlike psoralen plus UVA, which is usually reserved for postpartum use, narrowband UVB light therapy has been shown to be safe for use during pregnancy.¹ 

Future Directions

Genetic and pathogenesis studies have described involvement of IL-1 and IL-36 cytokines in GPP.¹ These interleukins are important in neutrophil chemotaxis leading to pustule formation.  In addition, as in other psoriasis variants, TNF-α and IL-17α are important. Such findings may help to pave the way for the development of future therapies for both GPP and PPP. 
 

Bottom Line

Clinicians should have a high index of suspicion for PPP in pregnant women who present with widespread cutaneous eruptions. Presently, oral corticosteroids paired with close involvement of obstetric care remains the cornerstone of treatment for PPP. As the case report illustrates, effective diagnosis, treatment, and monitoring are essential for safe outcomes for both mother and baby.
 

Real-world electronic health record data on tumor progression appears to be a good surrogate for overall survival, a finding that could help to improve estimates of benefit for complex cancer therapy regimens for use in both clinical trials and treatment planning, investigators say.

A study of electronic health record (EHR) data on more than 30,000 patients with non–small cell lung cancer (NSCLC) showed that real-world data on progression-free survival (PFS) showed a high degree of correlation with overall survival (OS), reported Sandra D. Griffith, PhD, of Flatiron Health, New York, and colleagues.

“As survival rates have improved and more than one therapy line has become typical, OS has become an inadequate metric for ascertaining the benefit of some cancer treatment interventions. Intermediate endpoints are essential for evaluating treatment benefits in real-world contexts. This study presents a scalable, feasible, and replicable approach to yield an EHR-generated progression variable ready for incorporation into large, contemporary real-world analyses,” they wrote in JCO Clinical Cancer Informatics.

The investigators studied retrospectively whether it would be feasible on a large scale to extract clinically relevant endpoints from an EHR-derived database that relies on technology-assisted abstraction of data from patient charts.

Their cohort included 30,276 patients diagnosed with advanced NSCLC from January 2011 through February 2018 who had two or more visits documented on EHR and who had been started on one or more lines of systemic therapy. Of this group, 16,606 had one or more documented tumor progression events, and 11,366 either died, discontinued therapy, or started on a new therapy.

The investigators found that among 20,000 evaluable patients, correlation of real-word PFS with OS was moderately high (Spearman’s P = .076), although for 11,902 patients with a progression event who died the correlation of EHR data with actual OS was somewhat lower (Spearman’s P = .069).

The strength of the correlations was verified in an duplicate random sample reviewed by independent abstractors.

The median time to abstract data on disease progression from individual electronic health records was 18 minutes.

“More work is needed to document how real-world progression under different treatments relates to treatment effects observed in clinical trials; understand the impact of different imaging and assessment cadences—for example, informative censoring; and clarify the relationship between real-world progression and other endpoints, such as real-world tumor response. Similar work is also needed in other tumor types,” Dr. Griffiths and colleagues wrote.

The study was supported by Flatiron Health, a subsidiary of Roche. Dr. Griffith and multiple co-authors are employees and stockholders of Flatiron Health and/or Roche.

SOURCE: Griffith SD et al. JCO Clinical Informatics. 2019 Aug 12. doi: 10.1200/CCI.19.00013.

Real-world electronic health record data on tumor progression appears to be a good surrogate for overall survival, a finding that could help to improve estimates of benefit for complex cancer therapy regimens for use in both clinical trials and treatment planning, investigators say.

A study of electronic health record (EHR) data on more than 30,000 patients with non–small cell lung cancer (NSCLC) showed that real-world data on progression-free survival (PFS) showed a high degree of correlation with overall survival (OS), reported Sandra D. Griffith, PhD, of Flatiron Health, New York, and colleagues.

“As survival rates have improved and more than one therapy line has become typical, OS has become an inadequate metric for ascertaining the benefit of some cancer treatment interventions. Intermediate endpoints are essential for evaluating treatment benefits in real-world contexts. This study presents a scalable, feasible, and replicable approach to yield an EHR-generated progression variable ready for incorporation into large, contemporary real-world analyses,” they wrote in JCO Clinical Cancer Informatics.

The investigators studied retrospectively whether it would be feasible on a large scale to extract clinically relevant endpoints from an EHR-derived database that relies on technology-assisted abstraction of data from patient charts.

Their cohort included 30,276 patients diagnosed with advanced NSCLC from January 2011 through February 2018 who had two or more visits documented on EHR and who had been started on one or more lines of systemic therapy. Of this group, 16,606 had one or more documented tumor progression events, and 11,366 either died, discontinued therapy, or started on a new therapy.

The investigators found that among 20,000 evaluable patients, correlation of real-word PFS with OS was moderately high (Spearman’s P = .076), although for 11,902 patients with a progression event who died the correlation of EHR data with actual OS was somewhat lower (Spearman’s P = .069).

The strength of the correlations was verified in an duplicate random sample reviewed by independent abstractors.

The median time to abstract data on disease progression from individual electronic health records was 18 minutes.

“More work is needed to document how real-world progression under different treatments relates to treatment effects observed in clinical trials; understand the impact of different imaging and assessment cadences—for example, informative censoring; and clarify the relationship between real-world progression and other endpoints, such as real-world tumor response. Similar work is also needed in other tumor types,” Dr. Griffiths and colleagues wrote.

The study was supported by Flatiron Health, a subsidiary of Roche. Dr. Griffith and multiple co-authors are employees and stockholders of Flatiron Health and/or Roche.

SOURCE: Griffith SD et al. JCO Clinical Informatics. 2019 Aug 12. doi: 10.1200/CCI.19.00013.

Real-world electronic health record data on tumor progression appears to be a good surrogate for overall survival, a finding that could help to improve estimates of benefit for complex cancer therapy regimens for use in both clinical trials and treatment planning, investigators say.

A study of electronic health record (EHR) data on more than 30,000 patients with non–small cell lung cancer (NSCLC) showed that real-world data on progression-free survival (PFS) showed a high degree of correlation with overall survival (OS), reported Sandra D. Griffith, PhD, of Flatiron Health, New York, and colleagues.

“As survival rates have improved and more than one therapy line has become typical, OS has become an inadequate metric for ascertaining the benefit of some cancer treatment interventions. Intermediate endpoints are essential for evaluating treatment benefits in real-world contexts. This study presents a scalable, feasible, and replicable approach to yield an EHR-generated progression variable ready for incorporation into large, contemporary real-world analyses,” they wrote in JCO Clinical Cancer Informatics.

The investigators studied retrospectively whether it would be feasible on a large scale to extract clinically relevant endpoints from an EHR-derived database that relies on technology-assisted abstraction of data from patient charts.

Their cohort included 30,276 patients diagnosed with advanced NSCLC from January 2011 through February 2018 who had two or more visits documented on EHR and who had been started on one or more lines of systemic therapy. Of this group, 16,606 had one or more documented tumor progression events, and 11,366 either died, discontinued therapy, or started on a new therapy.

The investigators found that among 20,000 evaluable patients, correlation of real-word PFS with OS was moderately high (Spearman’s P = .076), although for 11,902 patients with a progression event who died the correlation of EHR data with actual OS was somewhat lower (Spearman’s P = .069).

The strength of the correlations was verified in an duplicate random sample reviewed by independent abstractors.

The median time to abstract data on disease progression from individual electronic health records was 18 minutes.

“More work is needed to document how real-world progression under different treatments relates to treatment effects observed in clinical trials; understand the impact of different imaging and assessment cadences—for example, informative censoring; and clarify the relationship between real-world progression and other endpoints, such as real-world tumor response. Similar work is also needed in other tumor types,” Dr. Griffiths and colleagues wrote.

The study was supported by Flatiron Health, a subsidiary of Roche. Dr. Griffith and multiple co-authors are employees and stockholders of Flatiron Health and/or Roche.

SOURCE: Griffith SD et al. JCO Clinical Informatics. 2019 Aug 12. doi: 10.1200/CCI.19.00013.

ANSWER

The radiograph shows 3 abnormalities:

(1) The endotracheal tube is in the right mainstem bronchus—a finding that in part leads to

(2) A whiteout of the left lung; the latter is due partly to collapse and atelectasis and partly to a possible pneumothorax.

(3) There is evidence of free air under the left hemidiaphragm, which is concerning for an intra-abdominal injury, such as a perforated viscus.

The patient’s endotracheal tube was partially withdrawn, and a left chest tube was placed. Subsequent CT of the abdomen confirmed the finding of free air. She was then taken to the operating room for an emergent laparotomy.

ANSWER

The radiograph shows 3 abnormalities:

(1) The endotracheal tube is in the right mainstem bronchus—a finding that in part leads to

(2) A whiteout of the left lung; the latter is due partly to collapse and atelectasis and partly to a possible pneumothorax.

(3) There is evidence of free air under the left hemidiaphragm, which is concerning for an intra-abdominal injury, such as a perforated viscus.

The patient’s endotracheal tube was partially withdrawn, and a left chest tube was placed. Subsequent CT of the abdomen confirmed the finding of free air. She was then taken to the operating room for an emergent laparotomy.

ANSWER

The radiograph shows 3 abnormalities:

(1) The endotracheal tube is in the right mainstem bronchus—a finding that in part leads to

(2) A whiteout of the left lung; the latter is due partly to collapse and atelectasis and partly to a possible pneumothorax.

(3) There is evidence of free air under the left hemidiaphragm, which is concerning for an intra-abdominal injury, such as a perforated viscus.

The patient’s endotracheal tube was partially withdrawn, and a left chest tube was placed. Subsequent CT of the abdomen confirmed the finding of free air. She was then taken to the operating room for an emergent laparotomy.

An 88-year-old man with hypertension, chronic obstructive pulmonary disease, and atrial fibrillation presents with severe cerebral palsy and is diagnosed with a non–ST-elevation MI. He is found to have 90% left anterior descending artery occlusion and receives a drug-eluting stent. His current medications include warfarin, tiotropium, amlodipine, aspirin, and lisinopril. What anticoagulant therapy should he receive?

A) Clopidogrel, warfarin, and aspirin

B) Clopidogrel and aspirin

C) Clopidogrel and warfarin

D) Warfarin

E) Warfarin and aspirin

This issue comes up frequently with our patients with atrial fibrillation who are on anticoagulation, then have a coronary event and have a stent placed. What is the best approach to anticoagulation? I think for this patient adding clopidogrel, continuing warfarin, and stopping aspirin would be the best of the options presented.

Elderly patients have a higher risk of bleeding. They also have a greater chance of accumulating cardiovascular disease (atrial fibrillation, cardiac allograft vasculopathy, and valvular disease) that requires anticoagulation. Dewilde et al. studied the difference in bleeding risk in patients who were on oral anticoagulants who then underwent a percutaneous coronary intervention.¹ Patients were assigned clopidogrel alone or clopidogrel plus aspirin in addition to their oral anticoagulant (warfarin). There was a significant increase in all-cause mortality in the patients who received clopidogrel plus aspirin (P = .027), and no significant difference in cardiac mortality between the two groups. There was a much higher risk of bleeding (44.4%) in the patients receiving triple therapy, compared with the double-therapy group (19.4%; P less than .0001).

In a large meta-analysis of over 7,000 patients by D’Ascenzo et al., there was no difference in thrombotic risk between double and triple therapy, and lower bleeding risk in patients who received double therapy.²

In a recently published article, Lopes et al. looked at the benefits and risks of antithrombotic therapy after acute coronary syndrome or percutaneous coronary intervention in patients with atrial fibrillation.³ The study included 4,614 patients, all of whom received a P2Y12 inhibitor. In addition, they received either apixaban or warfarin, and either aspirin or placebo. The patients who received apixaban had a lower risk of bleeding than those receiving warfarin (P less than .001), and those receiving aspirin had a higher risk than those receiving placebo (hazard ratio, 1.89; P less than .001). Patients using the combination of apixaban plus placebo had the lowest event rate per 100 years (16.8), followed by warfarin plus placebo (26.7), then apixaban plus aspirin (33.6), with warfarin plus aspirin having the highest event rate (49.1). The conclusion for the study was that regimens with apixaban without aspirin had less bleeding and hospitalizations without increased ischemic events, compared with regimens of warfarin with or without aspirin.

I think it is best to avoid aspirin in patients who are anticoagulated with warfarin, and likely this extends to Xa inhibitors as well.

Pearl: Avoid using triple anticoagulant therapy by eliminating aspirin.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Dewilde WJ et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: An open-label, randomised, controlled trial. Lancet. 2013 Mar 30;381(9872):1107-15.

2. D’Ascenzo F et al. Meta-analysis of randomized controlled trials and adjusted observational results of use of clopidogrel, aspirin, and oral anticoagulants in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2015 May 1;115(9):1185-93.

3. Lopes RD et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-24.

An 88-year-old man with hypertension, chronic obstructive pulmonary disease, and atrial fibrillation presents with severe cerebral palsy and is diagnosed with a non–ST-elevation MI. He is found to have 90% left anterior descending artery occlusion and receives a drug-eluting stent. His current medications include warfarin, tiotropium, amlodipine, aspirin, and lisinopril. What anticoagulant therapy should he receive?

A) Clopidogrel, warfarin, and aspirin

B) Clopidogrel and aspirin

C) Clopidogrel and warfarin

D) Warfarin

E) Warfarin and aspirin

This issue comes up frequently with our patients with atrial fibrillation who are on anticoagulation, then have a coronary event and have a stent placed. What is the best approach to anticoagulation? I think for this patient adding clopidogrel, continuing warfarin, and stopping aspirin would be the best of the options presented.

Elderly patients have a higher risk of bleeding. They also have a greater chance of accumulating cardiovascular disease (atrial fibrillation, cardiac allograft vasculopathy, and valvular disease) that requires anticoagulation. Dewilde et al. studied the difference in bleeding risk in patients who were on oral anticoagulants who then underwent a percutaneous coronary intervention.¹ Patients were assigned clopidogrel alone or clopidogrel plus aspirin in addition to their oral anticoagulant (warfarin). There was a significant increase in all-cause mortality in the patients who received clopidogrel plus aspirin (P = .027), and no significant difference in cardiac mortality between the two groups. There was a much higher risk of bleeding (44.4%) in the patients receiving triple therapy, compared with the double-therapy group (19.4%; P less than .0001).

In a large meta-analysis of over 7,000 patients by D’Ascenzo et al., there was no difference in thrombotic risk between double and triple therapy, and lower bleeding risk in patients who received double therapy.²

In a recently published article, Lopes et al. looked at the benefits and risks of antithrombotic therapy after acute coronary syndrome or percutaneous coronary intervention in patients with atrial fibrillation.³ The study included 4,614 patients, all of whom received a P2Y12 inhibitor. In addition, they received either apixaban or warfarin, and either aspirin or placebo. The patients who received apixaban had a lower risk of bleeding than those receiving warfarin (P less than .001), and those receiving aspirin had a higher risk than those receiving placebo (hazard ratio, 1.89; P less than .001). Patients using the combination of apixaban plus placebo had the lowest event rate per 100 years (16.8), followed by warfarin plus placebo (26.7), then apixaban plus aspirin (33.6), with warfarin plus aspirin having the highest event rate (49.1). The conclusion for the study was that regimens with apixaban without aspirin had less bleeding and hospitalizations without increased ischemic events, compared with regimens of warfarin with or without aspirin.

I think it is best to avoid aspirin in patients who are anticoagulated with warfarin, and likely this extends to Xa inhibitors as well.

Pearl: Avoid using triple anticoagulant therapy by eliminating aspirin.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Dewilde WJ et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: An open-label, randomised, controlled trial. Lancet. 2013 Mar 30;381(9872):1107-15.

2. D’Ascenzo F et al. Meta-analysis of randomized controlled trials and adjusted observational results of use of clopidogrel, aspirin, and oral anticoagulants in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2015 May 1;115(9):1185-93.

3. Lopes RD et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-24.

An 88-year-old man with hypertension, chronic obstructive pulmonary disease, and atrial fibrillation presents with severe cerebral palsy and is diagnosed with a non–ST-elevation MI. He is found to have 90% left anterior descending artery occlusion and receives a drug-eluting stent. His current medications include warfarin, tiotropium, amlodipine, aspirin, and lisinopril. What anticoagulant therapy should he receive?

A) Clopidogrel, warfarin, and aspirin

B) Clopidogrel and aspirin

C) Clopidogrel and warfarin

D) Warfarin

E) Warfarin and aspirin

This issue comes up frequently with our patients with atrial fibrillation who are on anticoagulation, then have a coronary event and have a stent placed. What is the best approach to anticoagulation? I think for this patient adding clopidogrel, continuing warfarin, and stopping aspirin would be the best of the options presented.

Elderly patients have a higher risk of bleeding. They also have a greater chance of accumulating cardiovascular disease (atrial fibrillation, cardiac allograft vasculopathy, and valvular disease) that requires anticoagulation. Dewilde et al. studied the difference in bleeding risk in patients who were on oral anticoagulants who then underwent a percutaneous coronary intervention.¹ Patients were assigned clopidogrel alone or clopidogrel plus aspirin in addition to their oral anticoagulant (warfarin). There was a significant increase in all-cause mortality in the patients who received clopidogrel plus aspirin (P = .027), and no significant difference in cardiac mortality between the two groups. There was a much higher risk of bleeding (44.4%) in the patients receiving triple therapy, compared with the double-therapy group (19.4%; P less than .0001).

In a large meta-analysis of over 7,000 patients by D’Ascenzo et al., there was no difference in thrombotic risk between double and triple therapy, and lower bleeding risk in patients who received double therapy.²

In a recently published article, Lopes et al. looked at the benefits and risks of antithrombotic therapy after acute coronary syndrome or percutaneous coronary intervention in patients with atrial fibrillation.³ The study included 4,614 patients, all of whom received a P2Y12 inhibitor. In addition, they received either apixaban or warfarin, and either aspirin or placebo. The patients who received apixaban had a lower risk of bleeding than those receiving warfarin (P less than .001), and those receiving aspirin had a higher risk than those receiving placebo (hazard ratio, 1.89; P less than .001). Patients using the combination of apixaban plus placebo had the lowest event rate per 100 years (16.8), followed by warfarin plus placebo (26.7), then apixaban plus aspirin (33.6), with warfarin plus aspirin having the highest event rate (49.1). The conclusion for the study was that regimens with apixaban without aspirin had less bleeding and hospitalizations without increased ischemic events, compared with regimens of warfarin with or without aspirin.

I think it is best to avoid aspirin in patients who are anticoagulated with warfarin, and likely this extends to Xa inhibitors as well.

Pearl: Avoid using triple anticoagulant therapy by eliminating aspirin.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Dewilde WJ et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: An open-label, randomised, controlled trial. Lancet. 2013 Mar 30;381(9872):1107-15.

2. D’Ascenzo F et al. Meta-analysis of randomized controlled trials and adjusted observational results of use of clopidogrel, aspirin, and oral anticoagulants in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2015 May 1;115(9):1185-93.

3. Lopes RD et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-24.

LJUBLJANA, SLOVENIA – A point-of-care presepsin measurement in the emergency department displayed powerful accuracy for early rule-out of invasive bacterial infection in infants less than 3 months old presenting with fever without a source, based on results of a phase 3 multicenter Italian study.

Bruce Jancin/MDedge News

“P-SEP [presepsin] is a promising new biomarker. P-SEP accuracy for invasive bacterial infection is comparable to procalcitonin, even though P-SEP, like procalcitonin, is probably not accurate enough to be used as a stand-alone marker to rule-in an invasive bacterial infection,” Luca Pierantoni, MD, said in presenting the preliminary study results at the annual meeting of the European Society for Paediatric Infectious Diseases.

The presepsin test is a rapid point-of-care test well-suited for the ED setting, with a cost equal to that of point-of-care procalcitonin.

Presepsin is a form of soluble CD14 that is released from the surface of macrophages, monocytes, and neutrophils when these immune cells are stimulated by pathogens. “We think it may be a reliable diagnostic and prognostic marker of sepsis in adults and neonates,” explained Dr. Pierantoni of the University of Bologna, Italy.

Indeed, studies in adults suggest presepsin has better sensitivity and specificity than other biomarkers for early diagnosis of sepsis, and that it provides useful information on severity and prognosis as well. But, Dr. Pierantoni and his coworkers wondered, how does it perform in febrile young infants?

The Italian study was designed to address an unmet need: Fever accounts for about one-third of ED visits in infants up to age 3 months, 20% of whom are initially categorized as having fever without source. Yet ultimately 10%-20% of those youngsters having fever without source are found to have an invasive bacterial infection – that is, sepsis or meningitis – or a severe bacterial infection such as pneumonia, a urinary tract infection, or an infected umbilical cord. The sooner these infants can be identified and appropriately treated, the better.

The study enrolled 284 children less than 3 months old who had fever without cause of a mean 10.5 hours duration and presented to the emergency departments of six Italian medical centers. Children were eligible for the study regardless of whether they appeared toxic or well. Presepsin, procalcitonin, and C-reactive protein levels were immediately measured in all participants. Ultimately, 5.6% of subjects were diagnosed with an invasive bacterial infection, and another 21.2% had a severe bacterial infection.

Using a cutoff value of 449 pg/mL, P-SEP had good diagnostic accuracy for invasive bacterial infection, with an area under the receiver operating characteristics curve of 0.81, essentially the same as the 0.82 value for procalcitonin. P-SEP had a sensitivity and specificity of 87% and 75%, respectively, placing it in the same ballpark as the 82% and 86% values for procalcitonin. The strong point for P-SEP was its 99% negative predictive value, as compared to 91% for procalcitonin. The positive predictive values were 17% for P-SEP and 20% for procalcitonin.

In response to an audience question, Dr. Pierantoni speculated that the best use for P-SEP in the setting of fever of unknown origin may be in combination with procalcitonin rather than as a replacement for it. The research team is now in the process of analyzing their study data to see if that is indeed the case.

He reported having no financial conflicts regarding his study, conducted free of commercial support.

[email protected]

LJUBLJANA, SLOVENIA – A point-of-care presepsin measurement in the emergency department displayed powerful accuracy for early rule-out of invasive bacterial infection in infants less than 3 months old presenting with fever without a source, based on results of a phase 3 multicenter Italian study.

Bruce Jancin/MDedge News

“P-SEP [presepsin] is a promising new biomarker. P-SEP accuracy for invasive bacterial infection is comparable to procalcitonin, even though P-SEP, like procalcitonin, is probably not accurate enough to be used as a stand-alone marker to rule-in an invasive bacterial infection,” Luca Pierantoni, MD, said in presenting the preliminary study results at the annual meeting of the European Society for Paediatric Infectious Diseases.

The presepsin test is a rapid point-of-care test well-suited for the ED setting, with a cost equal to that of point-of-care procalcitonin.

Presepsin is a form of soluble CD14 that is released from the surface of macrophages, monocytes, and neutrophils when these immune cells are stimulated by pathogens. “We think it may be a reliable diagnostic and prognostic marker of sepsis in adults and neonates,” explained Dr. Pierantoni of the University of Bologna, Italy.

Indeed, studies in adults suggest presepsin has better sensitivity and specificity than other biomarkers for early diagnosis of sepsis, and that it provides useful information on severity and prognosis as well. But, Dr. Pierantoni and his coworkers wondered, how does it perform in febrile young infants?

The Italian study was designed to address an unmet need: Fever accounts for about one-third of ED visits in infants up to age 3 months, 20% of whom are initially categorized as having fever without source. Yet ultimately 10%-20% of those youngsters having fever without source are found to have an invasive bacterial infection – that is, sepsis or meningitis – or a severe bacterial infection such as pneumonia, a urinary tract infection, or an infected umbilical cord. The sooner these infants can be identified and appropriately treated, the better.

The study enrolled 284 children less than 3 months old who had fever without cause of a mean 10.5 hours duration and presented to the emergency departments of six Italian medical centers. Children were eligible for the study regardless of whether they appeared toxic or well. Presepsin, procalcitonin, and C-reactive protein levels were immediately measured in all participants. Ultimately, 5.6% of subjects were diagnosed with an invasive bacterial infection, and another 21.2% had a severe bacterial infection.

Using a cutoff value of 449 pg/mL, P-SEP had good diagnostic accuracy for invasive bacterial infection, with an area under the receiver operating characteristics curve of 0.81, essentially the same as the 0.82 value for procalcitonin. P-SEP had a sensitivity and specificity of 87% and 75%, respectively, placing it in the same ballpark as the 82% and 86% values for procalcitonin. The strong point for P-SEP was its 99% negative predictive value, as compared to 91% for procalcitonin. The positive predictive values were 17% for P-SEP and 20% for procalcitonin.

In response to an audience question, Dr. Pierantoni speculated that the best use for P-SEP in the setting of fever of unknown origin may be in combination with procalcitonin rather than as a replacement for it. The research team is now in the process of analyzing their study data to see if that is indeed the case.

He reported having no financial conflicts regarding his study, conducted free of commercial support.

[email protected]

LJUBLJANA, SLOVENIA – A point-of-care presepsin measurement in the emergency department displayed powerful accuracy for early rule-out of invasive bacterial infection in infants less than 3 months old presenting with fever without a source, based on results of a phase 3 multicenter Italian study.

Bruce Jancin/MDedge News

“P-SEP [presepsin] is a promising new biomarker. P-SEP accuracy for invasive bacterial infection is comparable to procalcitonin, even though P-SEP, like procalcitonin, is probably not accurate enough to be used as a stand-alone marker to rule-in an invasive bacterial infection,” Luca Pierantoni, MD, said in presenting the preliminary study results at the annual meeting of the European Society for Paediatric Infectious Diseases.

The presepsin test is a rapid point-of-care test well-suited for the ED setting, with a cost equal to that of point-of-care procalcitonin.

Presepsin is a form of soluble CD14 that is released from the surface of macrophages, monocytes, and neutrophils when these immune cells are stimulated by pathogens. “We think it may be a reliable diagnostic and prognostic marker of sepsis in adults and neonates,” explained Dr. Pierantoni of the University of Bologna, Italy.

Indeed, studies in adults suggest presepsin has better sensitivity and specificity than other biomarkers for early diagnosis of sepsis, and that it provides useful information on severity and prognosis as well. But, Dr. Pierantoni and his coworkers wondered, how does it perform in febrile young infants?

The Italian study was designed to address an unmet need: Fever accounts for about one-third of ED visits in infants up to age 3 months, 20% of whom are initially categorized as having fever without source. Yet ultimately 10%-20% of those youngsters having fever without source are found to have an invasive bacterial infection – that is, sepsis or meningitis – or a severe bacterial infection such as pneumonia, a urinary tract infection, or an infected umbilical cord. The sooner these infants can be identified and appropriately treated, the better.

The study enrolled 284 children less than 3 months old who had fever without cause of a mean 10.5 hours duration and presented to the emergency departments of six Italian medical centers. Children were eligible for the study regardless of whether they appeared toxic or well. Presepsin, procalcitonin, and C-reactive protein levels were immediately measured in all participants. Ultimately, 5.6% of subjects were diagnosed with an invasive bacterial infection, and another 21.2% had a severe bacterial infection.

Using a cutoff value of 449 pg/mL, P-SEP had good diagnostic accuracy for invasive bacterial infection, with an area under the receiver operating characteristics curve of 0.81, essentially the same as the 0.82 value for procalcitonin. P-SEP had a sensitivity and specificity of 87% and 75%, respectively, placing it in the same ballpark as the 82% and 86% values for procalcitonin. The strong point for P-SEP was its 99% negative predictive value, as compared to 91% for procalcitonin. The positive predictive values were 17% for P-SEP and 20% for procalcitonin.

In response to an audience question, Dr. Pierantoni speculated that the best use for P-SEP in the setting of fever of unknown origin may be in combination with procalcitonin rather than as a replacement for it. The research team is now in the process of analyzing their study data to see if that is indeed the case.

He reported having no financial conflicts regarding his study, conducted free of commercial support.

[email protected]

Fresher blood products are not necessarily better for patients with beta thalassemia, according to a pair of experts.

Red blood cell units stored less than 2 weeks are ideal, but older units are acceptable, and phenotype matching should take priority over unit age, advised Ashutosh Lal, MD, and Elliott Vichinsky, MD, both of UCSF Benioff Children’s Hospital Oakland (Calif.). They discussed these and other recommendations for transfusing patients with thalassemia during a webinar hosted by the Centers for Disease Control and Prevention.

Indications for transfusion

Dr. Lal said patients with beta thalassemia major should be transfused if their hemoglobin is less than 7 g/dL on two occasions 2 weeks apart at baseline, or if their hemoglobin is greater than 7 g/dL and they have symptoms of anemia.

Patients with hemoglobin E beta thalassemia major should be transfused only if they have symptoms of anemia.

“The rationale is that, in beta thalassemia major, it is well established that, once the hemoglobin levels fall below 7 g/dL in young children, there is going to be massive bone marrow expansion, and there will be severe symptoms from anemia,” Dr. Lal said. “But the relationship of hemoglobin with symptoms in E beta thalassemia is less precise.”

The symptoms that should prompt transfusion include slowed growth, skeletal facial changes, splenomegaly, symptomatic or moderate to severe extramedullary hematopoiesis, cerebrovascular events, venous thromboembolism, pulmonary hypertension, osteoporotic fracture, and impaired quality of life in adults.

Dr. Lal said physicians should consider a 6-month trial of transfusions if the indication is unclear. He also noted that red cell antigen genotyping should be performed in all patients who may need transfusions.

Blood products

Dr. Lal said beta thalassemia patients should receive packed red blood cells that are leukoreduced prior to storage. The storage solution can be citrate-phosphate-dextrose solution with adenine (hematocrit 75%) or additive solution (hematocrit 60%).

“It’s important to note that the hematocrit of the two is quite different, and that needs to be inculcated into the decisions on how much volume to transfuse to younger children,” Dr. Lal said.

He noted that units should not be irradiated, as this damages the red cell membrane. And patients with severe allergic reactions should receive washed red blood cells because washing units removes residual donor plasma proteins.

Finally, units should be less than 2 weeks old if possible. Dr. Lal said using fresh units increases the survival of red blood cells post transfusion. However, he and Dr. Vichinsky both stressed that older units are acceptable, and phenotype matching is more important than the age of the unit.

Phenotype matching

Beta thalassemia patients who do not have preexisting alloantibodies or have transient autoantibodies should be matched to Rh and Kell, according to Dr. Lal.

Patients with preexisting alloantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and the specific alloantibody. Patients with persistent autoantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and any alloantibody.

Patients who start transfusions after 5 years of age should be matched to Rh, Kell, Duffy, Kidd, and S. Pregnant patients should be matched to Rh, Kell, Duffy, Kidd, and S, and units should be cytomegalovirus negative.

How to transfuse

Dr. Lal said the pretransfusion hemoglobin target is 10 g/dL, with a range of 9.5-10.5 g/dL in beta thalassemia major and a range of 9.0-10.5 g/dL for E beta thalassemia. A target of 10 g/dL is adequate for most individuals, Dr. Lal said, but he recommends individualization of hemoglobin target for patients with E beta thalassemia.

In general, patients should be transfused every 3 weeks, although 4 weeks is acceptable in younger children and those with hemoglobin E beta thalassemia.

As for the volume of a transfusion, children should receive 4 mL per kg of body weight, per gram increase in hemoglobin desired. Partial units can be used to avoid undertransfusion.

For adults, in general, those with pretransfusion hemoglobin less than 10 g/dL should receive three units, and those with pretransfusion hemoglobin of 10 g/dL or greater should receive two units.

The hemoglobin threshold should be adjusted based on fatigue or bone pain, Dr. Lal said. He also noted that patients with intact spleens have higher transfusion needs.

The rate of transfusion should be 5 mL/kg/hour in children and 200-300 mL/hour in adults, based on tolerance. Patients with impaired cardiac function should receive a reduced blood volume at a reduced rate.

Non–transfusion dependent thalassemia

Dr. Vichinsky discussed recommendations for non–transfusion dependent thalassemia (NTDT), noting that these patients may need transient transfusions to prevent morbidity.

Hemoglobin should not be the sole determinant of transfusion need in NTDT patients, he said. Their well-being – activity level, growth, and skeletal changes – is more important than hemoglobin levels. However, patients with hemoglobin levels less than 7 g/dL often have severe morbidity, and those with levels of 10 g/dL or greater are usually protected from severe morbidity.

Indications for transfusion in NTDT patients include:
 

• Growth failure.
• Hematopoietic tumors.
• Pulmonary hypertension.
• Silent brain infarcts.
• Skin ulcers.
• Severe bone pain.
• Poor quality of life.
• Frequent hemolytic crises.
• Marked and enlarging spleen.
• Failure of secondary sex development.
• Cosmetic and facial changes.
• Pregnancy.

“There is a risk to transfusing this population,” Dr. Vichinsky said. “They’re older, and when you transfuse them, they can get iron overloaded.”

He added that splenectomized NTDT patients have a high risk of alloimmunization, and the transfusion duration should be serially reevaluated in NTDT patients.

Alpha thalassemia major

For alpha thalassemia major, Dr. Vichinsky discussed the importance of prevention, screening, and fetal therapy. He said couples with a fetus at risk of alpha thalassemia major should be identified early and offered, in addition to termination, the option of early fetal transfusion.

Dr. Vichinsky recommended prenatal testing and monitoring of at-risk pregnancies with ultrasound. If the fetus requires a transfusion, monitoring hemoglobin Barts and hemoglobin A is necessary.

A fetus that requires a transfusion should receive packed red blood cells that are cytomegalovirus negative, are less than 7 days old, have been irradiated, have a hemoglobin mass greater than 75%, and have been optimally cross matched with the mother first.

“These babies appear, with serial transfusions, to survive and have a relatively normal neonatal period,” Dr. Vichinsky said.

He added, however, that postnatal management of alpha thalassemia major involves an aggressive transfusion protocol. These patients should be transfused to a higher hemoglobin level than patients with beta thalassemia – roughly 12 g/dL versus 10 g/dL.

These and Dr. Lal’s recommendations are based on information in the Standards of Care Guidelines for Thalassemia – Oakland 2011, the Thalassemia International Federation Guidelines – 2014, the Thalassemia Management Checklists: United States – 2018, the Thalassemia Western Consortium Consensus: US – 2019, and the International Collaboration for Transfusion Medicine Guidelines – 2019.

Dr. Lal and Dr. Vichinsky did not disclose any conflicts of interest.

[email protected]

Fresher blood products are not necessarily better for patients with beta thalassemia, according to a pair of experts.

Red blood cell units stored less than 2 weeks are ideal, but older units are acceptable, and phenotype matching should take priority over unit age, advised Ashutosh Lal, MD, and Elliott Vichinsky, MD, both of UCSF Benioff Children’s Hospital Oakland (Calif.). They discussed these and other recommendations for transfusing patients with thalassemia during a webinar hosted by the Centers for Disease Control and Prevention.

Indications for transfusion

Dr. Lal said patients with beta thalassemia major should be transfused if their hemoglobin is less than 7 g/dL on two occasions 2 weeks apart at baseline, or if their hemoglobin is greater than 7 g/dL and they have symptoms of anemia.

Patients with hemoglobin E beta thalassemia major should be transfused only if they have symptoms of anemia.

“The rationale is that, in beta thalassemia major, it is well established that, once the hemoglobin levels fall below 7 g/dL in young children, there is going to be massive bone marrow expansion, and there will be severe symptoms from anemia,” Dr. Lal said. “But the relationship of hemoglobin with symptoms in E beta thalassemia is less precise.”

The symptoms that should prompt transfusion include slowed growth, skeletal facial changes, splenomegaly, symptomatic or moderate to severe extramedullary hematopoiesis, cerebrovascular events, venous thromboembolism, pulmonary hypertension, osteoporotic fracture, and impaired quality of life in adults.

Dr. Lal said physicians should consider a 6-month trial of transfusions if the indication is unclear. He also noted that red cell antigen genotyping should be performed in all patients who may need transfusions.

Blood products

Dr. Lal said beta thalassemia patients should receive packed red blood cells that are leukoreduced prior to storage. The storage solution can be citrate-phosphate-dextrose solution with adenine (hematocrit 75%) or additive solution (hematocrit 60%).

“It’s important to note that the hematocrit of the two is quite different, and that needs to be inculcated into the decisions on how much volume to transfuse to younger children,” Dr. Lal said.

He noted that units should not be irradiated, as this damages the red cell membrane. And patients with severe allergic reactions should receive washed red blood cells because washing units removes residual donor plasma proteins.

Finally, units should be less than 2 weeks old if possible. Dr. Lal said using fresh units increases the survival of red blood cells post transfusion. However, he and Dr. Vichinsky both stressed that older units are acceptable, and phenotype matching is more important than the age of the unit.

Phenotype matching

Beta thalassemia patients who do not have preexisting alloantibodies or have transient autoantibodies should be matched to Rh and Kell, according to Dr. Lal.

Patients with preexisting alloantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and the specific alloantibody. Patients with persistent autoantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and any alloantibody.

Patients who start transfusions after 5 years of age should be matched to Rh, Kell, Duffy, Kidd, and S. Pregnant patients should be matched to Rh, Kell, Duffy, Kidd, and S, and units should be cytomegalovirus negative.

How to transfuse

Dr. Lal said the pretransfusion hemoglobin target is 10 g/dL, with a range of 9.5-10.5 g/dL in beta thalassemia major and a range of 9.0-10.5 g/dL for E beta thalassemia. A target of 10 g/dL is adequate for most individuals, Dr. Lal said, but he recommends individualization of hemoglobin target for patients with E beta thalassemia.

In general, patients should be transfused every 3 weeks, although 4 weeks is acceptable in younger children and those with hemoglobin E beta thalassemia.

As for the volume of a transfusion, children should receive 4 mL per kg of body weight, per gram increase in hemoglobin desired. Partial units can be used to avoid undertransfusion.

For adults, in general, those with pretransfusion hemoglobin less than 10 g/dL should receive three units, and those with pretransfusion hemoglobin of 10 g/dL or greater should receive two units.

The hemoglobin threshold should be adjusted based on fatigue or bone pain, Dr. Lal said. He also noted that patients with intact spleens have higher transfusion needs.

The rate of transfusion should be 5 mL/kg/hour in children and 200-300 mL/hour in adults, based on tolerance. Patients with impaired cardiac function should receive a reduced blood volume at a reduced rate.

Non–transfusion dependent thalassemia

Dr. Vichinsky discussed recommendations for non–transfusion dependent thalassemia (NTDT), noting that these patients may need transient transfusions to prevent morbidity.

Hemoglobin should not be the sole determinant of transfusion need in NTDT patients, he said. Their well-being – activity level, growth, and skeletal changes – is more important than hemoglobin levels. However, patients with hemoglobin levels less than 7 g/dL often have severe morbidity, and those with levels of 10 g/dL or greater are usually protected from severe morbidity.

Indications for transfusion in NTDT patients include:
 

• Growth failure.
• Hematopoietic tumors.
• Pulmonary hypertension.
• Silent brain infarcts.
• Skin ulcers.
• Severe bone pain.
• Poor quality of life.
• Frequent hemolytic crises.
• Marked and enlarging spleen.
• Failure of secondary sex development.
• Cosmetic and facial changes.
• Pregnancy.

“There is a risk to transfusing this population,” Dr. Vichinsky said. “They’re older, and when you transfuse them, they can get iron overloaded.”

He added that splenectomized NTDT patients have a high risk of alloimmunization, and the transfusion duration should be serially reevaluated in NTDT patients.

Alpha thalassemia major

For alpha thalassemia major, Dr. Vichinsky discussed the importance of prevention, screening, and fetal therapy. He said couples with a fetus at risk of alpha thalassemia major should be identified early and offered, in addition to termination, the option of early fetal transfusion.

Dr. Vichinsky recommended prenatal testing and monitoring of at-risk pregnancies with ultrasound. If the fetus requires a transfusion, monitoring hemoglobin Barts and hemoglobin A is necessary.

A fetus that requires a transfusion should receive packed red blood cells that are cytomegalovirus negative, are less than 7 days old, have been irradiated, have a hemoglobin mass greater than 75%, and have been optimally cross matched with the mother first.

“These babies appear, with serial transfusions, to survive and have a relatively normal neonatal period,” Dr. Vichinsky said.

He added, however, that postnatal management of alpha thalassemia major involves an aggressive transfusion protocol. These patients should be transfused to a higher hemoglobin level than patients with beta thalassemia – roughly 12 g/dL versus 10 g/dL.

These and Dr. Lal’s recommendations are based on information in the Standards of Care Guidelines for Thalassemia – Oakland 2011, the Thalassemia International Federation Guidelines – 2014, the Thalassemia Management Checklists: United States – 2018, the Thalassemia Western Consortium Consensus: US – 2019, and the International Collaboration for Transfusion Medicine Guidelines – 2019.

Dr. Lal and Dr. Vichinsky did not disclose any conflicts of interest.

[email protected]

Fresher blood products are not necessarily better for patients with beta thalassemia, according to a pair of experts.

Red blood cell units stored less than 2 weeks are ideal, but older units are acceptable, and phenotype matching should take priority over unit age, advised Ashutosh Lal, MD, and Elliott Vichinsky, MD, both of UCSF Benioff Children’s Hospital Oakland (Calif.). They discussed these and other recommendations for transfusing patients with thalassemia during a webinar hosted by the Centers for Disease Control and Prevention.

Indications for transfusion

Dr. Lal said patients with beta thalassemia major should be transfused if their hemoglobin is less than 7 g/dL on two occasions 2 weeks apart at baseline, or if their hemoglobin is greater than 7 g/dL and they have symptoms of anemia.

Patients with hemoglobin E beta thalassemia major should be transfused only if they have symptoms of anemia.

“The rationale is that, in beta thalassemia major, it is well established that, once the hemoglobin levels fall below 7 g/dL in young children, there is going to be massive bone marrow expansion, and there will be severe symptoms from anemia,” Dr. Lal said. “But the relationship of hemoglobin with symptoms in E beta thalassemia is less precise.”

The symptoms that should prompt transfusion include slowed growth, skeletal facial changes, splenomegaly, symptomatic or moderate to severe extramedullary hematopoiesis, cerebrovascular events, venous thromboembolism, pulmonary hypertension, osteoporotic fracture, and impaired quality of life in adults.

Dr. Lal said physicians should consider a 6-month trial of transfusions if the indication is unclear. He also noted that red cell antigen genotyping should be performed in all patients who may need transfusions.

Blood products

Dr. Lal said beta thalassemia patients should receive packed red blood cells that are leukoreduced prior to storage. The storage solution can be citrate-phosphate-dextrose solution with adenine (hematocrit 75%) or additive solution (hematocrit 60%).

“It’s important to note that the hematocrit of the two is quite different, and that needs to be inculcated into the decisions on how much volume to transfuse to younger children,” Dr. Lal said.

He noted that units should not be irradiated, as this damages the red cell membrane. And patients with severe allergic reactions should receive washed red blood cells because washing units removes residual donor plasma proteins.

Finally, units should be less than 2 weeks old if possible. Dr. Lal said using fresh units increases the survival of red blood cells post transfusion. However, he and Dr. Vichinsky both stressed that older units are acceptable, and phenotype matching is more important than the age of the unit.

Phenotype matching

Beta thalassemia patients who do not have preexisting alloantibodies or have transient autoantibodies should be matched to Rh and Kell, according to Dr. Lal.

Patients with preexisting alloantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and the specific alloantibody. Patients with persistent autoantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and any alloantibody.

Patients who start transfusions after 5 years of age should be matched to Rh, Kell, Duffy, Kidd, and S. Pregnant patients should be matched to Rh, Kell, Duffy, Kidd, and S, and units should be cytomegalovirus negative.

How to transfuse

Dr. Lal said the pretransfusion hemoglobin target is 10 g/dL, with a range of 9.5-10.5 g/dL in beta thalassemia major and a range of 9.0-10.5 g/dL for E beta thalassemia. A target of 10 g/dL is adequate for most individuals, Dr. Lal said, but he recommends individualization of hemoglobin target for patients with E beta thalassemia.

In general, patients should be transfused every 3 weeks, although 4 weeks is acceptable in younger children and those with hemoglobin E beta thalassemia.

As for the volume of a transfusion, children should receive 4 mL per kg of body weight, per gram increase in hemoglobin desired. Partial units can be used to avoid undertransfusion.

For adults, in general, those with pretransfusion hemoglobin less than 10 g/dL should receive three units, and those with pretransfusion hemoglobin of 10 g/dL or greater should receive two units.

The hemoglobin threshold should be adjusted based on fatigue or bone pain, Dr. Lal said. He also noted that patients with intact spleens have higher transfusion needs.

The rate of transfusion should be 5 mL/kg/hour in children and 200-300 mL/hour in adults, based on tolerance. Patients with impaired cardiac function should receive a reduced blood volume at a reduced rate.

Non–transfusion dependent thalassemia

Dr. Vichinsky discussed recommendations for non–transfusion dependent thalassemia (NTDT), noting that these patients may need transient transfusions to prevent morbidity.

Hemoglobin should not be the sole determinant of transfusion need in NTDT patients, he said. Their well-being – activity level, growth, and skeletal changes – is more important than hemoglobin levels. However, patients with hemoglobin levels less than 7 g/dL often have severe morbidity, and those with levels of 10 g/dL or greater are usually protected from severe morbidity.

Indications for transfusion in NTDT patients include:
 

• Growth failure.
• Hematopoietic tumors.
• Pulmonary hypertension.
• Silent brain infarcts.
• Skin ulcers.
• Severe bone pain.
• Poor quality of life.
• Frequent hemolytic crises.
• Marked and enlarging spleen.
• Failure of secondary sex development.
• Cosmetic and facial changes.
• Pregnancy.

“There is a risk to transfusing this population,” Dr. Vichinsky said. “They’re older, and when you transfuse them, they can get iron overloaded.”

He added that splenectomized NTDT patients have a high risk of alloimmunization, and the transfusion duration should be serially reevaluated in NTDT patients.

Alpha thalassemia major

For alpha thalassemia major, Dr. Vichinsky discussed the importance of prevention, screening, and fetal therapy. He said couples with a fetus at risk of alpha thalassemia major should be identified early and offered, in addition to termination, the option of early fetal transfusion.

Dr. Vichinsky recommended prenatal testing and monitoring of at-risk pregnancies with ultrasound. If the fetus requires a transfusion, monitoring hemoglobin Barts and hemoglobin A is necessary.

A fetus that requires a transfusion should receive packed red blood cells that are cytomegalovirus negative, are less than 7 days old, have been irradiated, have a hemoglobin mass greater than 75%, and have been optimally cross matched with the mother first.

“These babies appear, with serial transfusions, to survive and have a relatively normal neonatal period,” Dr. Vichinsky said.

He added, however, that postnatal management of alpha thalassemia major involves an aggressive transfusion protocol. These patients should be transfused to a higher hemoglobin level than patients with beta thalassemia – roughly 12 g/dL versus 10 g/dL.

These and Dr. Lal’s recommendations are based on information in the Standards of Care Guidelines for Thalassemia – Oakland 2011, the Thalassemia International Federation Guidelines – 2014, the Thalassemia Management Checklists: United States – 2018, the Thalassemia Western Consortium Consensus: US – 2019, and the International Collaboration for Transfusion Medicine Guidelines – 2019.

Dr. Lal and Dr. Vichinsky did not disclose any conflicts of interest.

[email protected]

It has been 40 years since the first reported case of IgE-mediated natural rubber latex allergy, which was soon followed by a global epidemic of allergic and anaphylactic reactions.^1,2 Resolution came through insightful work in the 1990s that led to the removal of cornstarch powder and a switch to nonpowdered latex and synthetic examination gloves.² Also discovered during this period was the cross-reactivity of many patients to latex and various fruits. This column will briefly discuss the latex/fruit allergy syndrome, which should be considered in patients who are sensitive to various skincare products.

tookapic/Pixabay

Research substantiates reports

Blanco et al. conducted a prospective study in their outpatient clinic in 25 patients diagnosed with latex allergy, published in 1994.They used a clinical questionnaire, skin-prick tests, skin test with a latex extract, and identification of total and specific IgE to help ascertain clinical characteristics and cross-reactivity. Of the 23 women and 2 men in the study (mean age 33, plus or minus 9 years), 9 (36%) experienced latex-induced reactions characterized by systemic anaphylaxis. In 13 patients (52%), 42 food allergies were identified, and 23 included systemic anaphylaxis. Avocado (9), chestnut (9), banana (7), kiwi (5), and papaya (3) were the most common foods to cause hypersensitivities. The researchers concluded that their small study supported the reality of a “latex-fruit syndrome.”³

Another study aimed to characterize the cross-reactivity of latex and foods and evaluate clinical significance. Beezhold et al. examined 47 patients allergic to latex and 46 nonallergic controls. The investigators found immunologic reactivity to foods to be prevalent (33 latex-allergic patients and seven controls), with 27% of food skin-prick tests positive in the latex-allergic group. In addition, clinical symptoms were linked to 27% of positive skin-prick tests. Among the 17 patients who displayed clinical allergies to at least one food, 14 showed local sensitivity reactions, with anaphylaxis noted in 11. Avocado (53%), potato (40%), banana (38%), tomato (28%), chestnut (28%), and kiwi (17%) were the foods most frequently cited for provoking a skin test reaction. The authors observed extensive cross-reactivity between latex sensitivity and particular foods, with potatoes and tomatoes reported for the first time.⁴

In 1997, Brehler et al. studied serum samples from 136 patients whose immediate hypersensitivity to latex proteins was clinically observable and documented. The samples were assessed for IgE antibodies against several fruits, with fruit-specific IgE antibodies recorded in 69.1%. Radioallergosorbent (RAST) -inhibition tests yielded the recognition of cross-reacting IgE antibodies in latex and multiple fruit allergens: avocado, banana, chestnut, fig, kiwi, mango, melon, papaya, passion fruit, peach, pineapple, and tomato. The investigators recorded 112 intolerance reactions and noted that 42.5% of their patients reported allergic symptoms after consuming these fruits. Fruit-specific IgE antibodies were detected in only 32.1% of these patients, suggesting to the researchers that serologic tests were suboptimal in forecasting food hypersensitivities in patients who are allergic to latex.⁵

Cross-reactivity with banana

Mäkinen-Kiljunen studied 47 patients to investigate banana allergy in patients with latex allergy in 1994, measuring latex-, banana-, and pollen-specific (birch, timothy, and mugwort) IgE. Thirty-one patients were also given skin-prick tests with banana and were queried about reactions after consuming bananas. Of the 47 sera samples, latex RAST results were positive in 31 and banana RAST results in 26. RAST results from latex and banana were correlated (25 of the 31 latex RAST-positive samples were also banana RAST-positive), but not with pollen. Sixteen of the 31 patients who ate banana reported symptoms, and 11 of the 31 patients given the banana skin-prick test showed positive results. The author confirmed the cross-reactivity of IgE antibodies for latex and banana, identifying for the first time a structurally similar antigen/allergen as at least one antigen from banana fused with an antigen from latex in crossed-line immunoelectrophoresis.⁶

In 1998, Mikkola et al. investigated whether proteins similar to hevein, a major natural rubber latex allergen, are present in banana and account for cross-reactivity between these botanicals. Immunoblotting revealed that 9 of 15 sera from latex-allergic patients with IgE to hevein also bound to 32- and 33-kd banana proteins. Studies using ELISA [enzyme-linked immunosorbent assay] showed that the common presentation of hypersensitivity to banana among patients allergic to latex could be attributed to cross-reacting IgE antibodies binding to epitopes in hevein and in the then-newly identified hevein-like endochitinase found in banana.⁷

Cross-reactivity with avocado

In response to reports of an association between allergy to natural rubber latex and avocado, Ahlroth et al. investigated cross-reactive proteins between natural rubber latex and avocado in 1995 by using skin-prick tests with fresh avocado on 11 patients and the sera of 18 patients with known latex allergy for IgE antibodies. Fourteen of the 18 sera were found to have IgE antibodies binding to 17 distinct avocado proteins, with multiple immunoblot experiments and skin-prick test results (positive in 7 of 11 patients) revealing marked immunologic cross-reactivity between latex and avocado.⁸

In 1998, Chen et al. set out to identify the cross-sensitizing allergen between latex and avocado, with hevein suspected. The researchers looked at sera samples from 118 health care workers allergic to latex and 78 patients with spina bifida who were allergic to latex. They noted a robust correlation between the prevalence of seropositive IgE antibodies to avocado in the presence of hevein-specific IgE antibodies in both groups. All members in the spina bifida group and 91 (73%) of the health care workers had positive IgE antibodies to hevein and high IgE values to avocado. Additional results supported the conclusion that sensitization to avocado in the majority of people allergic to latex is engendered by IgE-binding epitopes found in hevein.⁹

A year later, Diaz-Perales et al. considered the potential relevance of chitinases and complex glycans as factors in the then newly described latex/food syndrome, particularly in avocado, banana, and chestnuts. The investigators culled extracts from 20 various plant foods as well as latex. In immunoblot inhibition assays, the primary allergen and class I chitinase in avocado, Prs a 1, and the latex extract potently or completely blocked IgE binding by these constituents. Polyclonal antibodies to chitinases and sera from patients with latex/fruit allergy responded to reactive proteins of about 30-45 kd (putative class I chitinases) in chestnut, cherimoya, kiwi, mango, papaya, passion fruit, tomato, and wheat flour extracts. The glycans complex was deemed to be irrelevant in latex/fruit cross-reactivity, but the researchers found the putative class I chitinases to be notable players in the latex/fruit syndrome.¹⁰

According to Wagner and Breitender, anywhere from 30%-50% of people with known latex allergy also evince a related hypersensitivity or allergy to various plant-derived foods, with avocado, banana, chestnut, kiwi, peach, tomato, potato, and bell pepper among the foods most frequently linked to latex/fruit syndrome. They summarize that several plant defense proteins have been shown to be involved in the syndrome, with the most prominent, class I chitinases with an N-terminal hevein-like domain, having been found to cross-react with hevein (Hev b 6.02), a major IgE-binding allergen for individuals allergic to latex. A beta-1,3-glucanase, a key latex allergen, has also shown cross-reactivity with proteins of bell pepper, and another significant latex allergen, Hev b 7, a patatin-like protein, cross-reacts with its analogous protein in potato.¹¹

Conclusion

It is unknown whether latex allergy precedes or follows food allergy.11 The latex/food syndrome itself merits attention as a significant source of hypersensitivity to natural cosmeceutical ingredients. Dermatologists should be aware of the lengthy list of cross-reacting plant-derived products, particularly when it comes to reviewing topical product ingredients with susceptible or allergic patients. Latex-allergic patients may react to these natural ingredients in food or when topically applied to the skin.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at [email protected].

References

1. Nutter AF. Br J Dermatol 1979 Nov;101(5):597-8.

2. Kelly KJ et al. J Allergy Clin Immunol Pract. 2017 Sep-Oct;5(5):1212-16.

3. Blanco C et al. Ann Allergy. 1994 Oct;73(4):309-14.

4. Beezhold DH et al. Clin Exp Allergy. 1996 Apr;26(4):416-22.

5. Brehler R et al. Allergy. 1997 Apr;52(4):404-10.

6. Mäkinen-Kiljunen S. J Allergy Clin Immunol. 1994 Jun;93(6):990-6.

7. Mikkola JH et al. J Allergy Clin Immunol. 1998 Dec;102(6 Pt 1):1005-12.

8. Ahlroth M et al. J Allergy Clin Immunol. 1995 Aug;96(2):167-73.

9. Chen Z et al. J Allergy Clin Immunol. 1998 Sep;102(3):476-81.

10. Diaz-Perales A et al. J Allergy Clin Immunol. 1999 Sep;104(3 Pt 1):681-7.

11. Wagner S et al. Biochem Soc Trans. 2002 Nov;30(Pt 6):935-40.

It has been 40 years since the first reported case of IgE-mediated natural rubber latex allergy, which was soon followed by a global epidemic of allergic and anaphylactic reactions.^1,2 Resolution came through insightful work in the 1990s that led to the removal of cornstarch powder and a switch to nonpowdered latex and synthetic examination gloves.² Also discovered during this period was the cross-reactivity of many patients to latex and various fruits. This column will briefly discuss the latex/fruit allergy syndrome, which should be considered in patients who are sensitive to various skincare products.

tookapic/Pixabay

Research substantiates reports

Blanco et al. conducted a prospective study in their outpatient clinic in 25 patients diagnosed with latex allergy, published in 1994.They used a clinical questionnaire, skin-prick tests, skin test with a latex extract, and identification of total and specific IgE to help ascertain clinical characteristics and cross-reactivity. Of the 23 women and 2 men in the study (mean age 33, plus or minus 9 years), 9 (36%) experienced latex-induced reactions characterized by systemic anaphylaxis. In 13 patients (52%), 42 food allergies were identified, and 23 included systemic anaphylaxis. Avocado (9), chestnut (9), banana (7), kiwi (5), and papaya (3) were the most common foods to cause hypersensitivities. The researchers concluded that their small study supported the reality of a “latex-fruit syndrome.”³

Another study aimed to characterize the cross-reactivity of latex and foods and evaluate clinical significance. Beezhold et al. examined 47 patients allergic to latex and 46 nonallergic controls. The investigators found immunologic reactivity to foods to be prevalent (33 latex-allergic patients and seven controls), with 27% of food skin-prick tests positive in the latex-allergic group. In addition, clinical symptoms were linked to 27% of positive skin-prick tests. Among the 17 patients who displayed clinical allergies to at least one food, 14 showed local sensitivity reactions, with anaphylaxis noted in 11. Avocado (53%), potato (40%), banana (38%), tomato (28%), chestnut (28%), and kiwi (17%) were the foods most frequently cited for provoking a skin test reaction. The authors observed extensive cross-reactivity between latex sensitivity and particular foods, with potatoes and tomatoes reported for the first time.⁴

In 1997, Brehler et al. studied serum samples from 136 patients whose immediate hypersensitivity to latex proteins was clinically observable and documented. The samples were assessed for IgE antibodies against several fruits, with fruit-specific IgE antibodies recorded in 69.1%. Radioallergosorbent (RAST) -inhibition tests yielded the recognition of cross-reacting IgE antibodies in latex and multiple fruit allergens: avocado, banana, chestnut, fig, kiwi, mango, melon, papaya, passion fruit, peach, pineapple, and tomato. The investigators recorded 112 intolerance reactions and noted that 42.5% of their patients reported allergic symptoms after consuming these fruits. Fruit-specific IgE antibodies were detected in only 32.1% of these patients, suggesting to the researchers that serologic tests were suboptimal in forecasting food hypersensitivities in patients who are allergic to latex.⁵

Cross-reactivity with banana

Mäkinen-Kiljunen studied 47 patients to investigate banana allergy in patients with latex allergy in 1994, measuring latex-, banana-, and pollen-specific (birch, timothy, and mugwort) IgE. Thirty-one patients were also given skin-prick tests with banana and were queried about reactions after consuming bananas. Of the 47 sera samples, latex RAST results were positive in 31 and banana RAST results in 26. RAST results from latex and banana were correlated (25 of the 31 latex RAST-positive samples were also banana RAST-positive), but not with pollen. Sixteen of the 31 patients who ate banana reported symptoms, and 11 of the 31 patients given the banana skin-prick test showed positive results. The author confirmed the cross-reactivity of IgE antibodies for latex and banana, identifying for the first time a structurally similar antigen/allergen as at least one antigen from banana fused with an antigen from latex in crossed-line immunoelectrophoresis.⁶

In 1998, Mikkola et al. investigated whether proteins similar to hevein, a major natural rubber latex allergen, are present in banana and account for cross-reactivity between these botanicals. Immunoblotting revealed that 9 of 15 sera from latex-allergic patients with IgE to hevein also bound to 32- and 33-kd banana proteins. Studies using ELISA [enzyme-linked immunosorbent assay] showed that the common presentation of hypersensitivity to banana among patients allergic to latex could be attributed to cross-reacting IgE antibodies binding to epitopes in hevein and in the then-newly identified hevein-like endochitinase found in banana.⁷

Cross-reactivity with avocado

In response to reports of an association between allergy to natural rubber latex and avocado, Ahlroth et al. investigated cross-reactive proteins between natural rubber latex and avocado in 1995 by using skin-prick tests with fresh avocado on 11 patients and the sera of 18 patients with known latex allergy for IgE antibodies. Fourteen of the 18 sera were found to have IgE antibodies binding to 17 distinct avocado proteins, with multiple immunoblot experiments and skin-prick test results (positive in 7 of 11 patients) revealing marked immunologic cross-reactivity between latex and avocado.⁸

In 1998, Chen et al. set out to identify the cross-sensitizing allergen between latex and avocado, with hevein suspected. The researchers looked at sera samples from 118 health care workers allergic to latex and 78 patients with spina bifida who were allergic to latex. They noted a robust correlation between the prevalence of seropositive IgE antibodies to avocado in the presence of hevein-specific IgE antibodies in both groups. All members in the spina bifida group and 91 (73%) of the health care workers had positive IgE antibodies to hevein and high IgE values to avocado. Additional results supported the conclusion that sensitization to avocado in the majority of people allergic to latex is engendered by IgE-binding epitopes found in hevein.⁹

A year later, Diaz-Perales et al. considered the potential relevance of chitinases and complex glycans as factors in the then newly described latex/food syndrome, particularly in avocado, banana, and chestnuts. The investigators culled extracts from 20 various plant foods as well as latex. In immunoblot inhibition assays, the primary allergen and class I chitinase in avocado, Prs a 1, and the latex extract potently or completely blocked IgE binding by these constituents. Polyclonal antibodies to chitinases and sera from patients with latex/fruit allergy responded to reactive proteins of about 30-45 kd (putative class I chitinases) in chestnut, cherimoya, kiwi, mango, papaya, passion fruit, tomato, and wheat flour extracts. The glycans complex was deemed to be irrelevant in latex/fruit cross-reactivity, but the researchers found the putative class I chitinases to be notable players in the latex/fruit syndrome.¹⁰

According to Wagner and Breitender, anywhere from 30%-50% of people with known latex allergy also evince a related hypersensitivity or allergy to various plant-derived foods, with avocado, banana, chestnut, kiwi, peach, tomato, potato, and bell pepper among the foods most frequently linked to latex/fruit syndrome. They summarize that several plant defense proteins have been shown to be involved in the syndrome, with the most prominent, class I chitinases with an N-terminal hevein-like domain, having been found to cross-react with hevein (Hev b 6.02), a major IgE-binding allergen for individuals allergic to latex. A beta-1,3-glucanase, a key latex allergen, has also shown cross-reactivity with proteins of bell pepper, and another significant latex allergen, Hev b 7, a patatin-like protein, cross-reacts with its analogous protein in potato.¹¹

Conclusion

It is unknown whether latex allergy precedes or follows food allergy.11 The latex/food syndrome itself merits attention as a significant source of hypersensitivity to natural cosmeceutical ingredients. Dermatologists should be aware of the lengthy list of cross-reacting plant-derived products, particularly when it comes to reviewing topical product ingredients with susceptible or allergic patients. Latex-allergic patients may react to these natural ingredients in food or when topically applied to the skin.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at [email protected].

References

1. Nutter AF. Br J Dermatol 1979 Nov;101(5):597-8.

2. Kelly KJ et al. J Allergy Clin Immunol Pract. 2017 Sep-Oct;5(5):1212-16.

3. Blanco C et al. Ann Allergy. 1994 Oct;73(4):309-14.

4. Beezhold DH et al. Clin Exp Allergy. 1996 Apr;26(4):416-22.

5. Brehler R et al. Allergy. 1997 Apr;52(4):404-10.

6. Mäkinen-Kiljunen S. J Allergy Clin Immunol. 1994 Jun;93(6):990-6.

7. Mikkola JH et al. J Allergy Clin Immunol. 1998 Dec;102(6 Pt 1):1005-12.

8. Ahlroth M et al. J Allergy Clin Immunol. 1995 Aug;96(2):167-73.

9. Chen Z et al. J Allergy Clin Immunol. 1998 Sep;102(3):476-81.

10. Diaz-Perales A et al. J Allergy Clin Immunol. 1999 Sep;104(3 Pt 1):681-7.

11. Wagner S et al. Biochem Soc Trans. 2002 Nov;30(Pt 6):935-40.

It has been 40 years since the first reported case of IgE-mediated natural rubber latex allergy, which was soon followed by a global epidemic of allergic and anaphylactic reactions.^1,2 Resolution came through insightful work in the 1990s that led to the removal of cornstarch powder and a switch to nonpowdered latex and synthetic examination gloves.² Also discovered during this period was the cross-reactivity of many patients to latex and various fruits. This column will briefly discuss the latex/fruit allergy syndrome, which should be considered in patients who are sensitive to various skincare products.

tookapic/Pixabay

Research substantiates reports

Blanco et al. conducted a prospective study in their outpatient clinic in 25 patients diagnosed with latex allergy, published in 1994.They used a clinical questionnaire, skin-prick tests, skin test with a latex extract, and identification of total and specific IgE to help ascertain clinical characteristics and cross-reactivity. Of the 23 women and 2 men in the study (mean age 33, plus or minus 9 years), 9 (36%) experienced latex-induced reactions characterized by systemic anaphylaxis. In 13 patients (52%), 42 food allergies were identified, and 23 included systemic anaphylaxis. Avocado (9), chestnut (9), banana (7), kiwi (5), and papaya (3) were the most common foods to cause hypersensitivities. The researchers concluded that their small study supported the reality of a “latex-fruit syndrome.”³

Another study aimed to characterize the cross-reactivity of latex and foods and evaluate clinical significance. Beezhold et al. examined 47 patients allergic to latex and 46 nonallergic controls. The investigators found immunologic reactivity to foods to be prevalent (33 latex-allergic patients and seven controls), with 27% of food skin-prick tests positive in the latex-allergic group. In addition, clinical symptoms were linked to 27% of positive skin-prick tests. Among the 17 patients who displayed clinical allergies to at least one food, 14 showed local sensitivity reactions, with anaphylaxis noted in 11. Avocado (53%), potato (40%), banana (38%), tomato (28%), chestnut (28%), and kiwi (17%) were the foods most frequently cited for provoking a skin test reaction. The authors observed extensive cross-reactivity between latex sensitivity and particular foods, with potatoes and tomatoes reported for the first time.⁴

In 1997, Brehler et al. studied serum samples from 136 patients whose immediate hypersensitivity to latex proteins was clinically observable and documented. The samples were assessed for IgE antibodies against several fruits, with fruit-specific IgE antibodies recorded in 69.1%. Radioallergosorbent (RAST) -inhibition tests yielded the recognition of cross-reacting IgE antibodies in latex and multiple fruit allergens: avocado, banana, chestnut, fig, kiwi, mango, melon, papaya, passion fruit, peach, pineapple, and tomato. The investigators recorded 112 intolerance reactions and noted that 42.5% of their patients reported allergic symptoms after consuming these fruits. Fruit-specific IgE antibodies were detected in only 32.1% of these patients, suggesting to the researchers that serologic tests were suboptimal in forecasting food hypersensitivities in patients who are allergic to latex.⁵

Cross-reactivity with banana

Mäkinen-Kiljunen studied 47 patients to investigate banana allergy in patients with latex allergy in 1994, measuring latex-, banana-, and pollen-specific (birch, timothy, and mugwort) IgE. Thirty-one patients were also given skin-prick tests with banana and were queried about reactions after consuming bananas. Of the 47 sera samples, latex RAST results were positive in 31 and banana RAST results in 26. RAST results from latex and banana were correlated (25 of the 31 latex RAST-positive samples were also banana RAST-positive), but not with pollen. Sixteen of the 31 patients who ate banana reported symptoms, and 11 of the 31 patients given the banana skin-prick test showed positive results. The author confirmed the cross-reactivity of IgE antibodies for latex and banana, identifying for the first time a structurally similar antigen/allergen as at least one antigen from banana fused with an antigen from latex in crossed-line immunoelectrophoresis.⁶

In 1998, Mikkola et al. investigated whether proteins similar to hevein, a major natural rubber latex allergen, are present in banana and account for cross-reactivity between these botanicals. Immunoblotting revealed that 9 of 15 sera from latex-allergic patients with IgE to hevein also bound to 32- and 33-kd banana proteins. Studies using ELISA [enzyme-linked immunosorbent assay] showed that the common presentation of hypersensitivity to banana among patients allergic to latex could be attributed to cross-reacting IgE antibodies binding to epitopes in hevein and in the then-newly identified hevein-like endochitinase found in banana.⁷

Cross-reactivity with avocado

In response to reports of an association between allergy to natural rubber latex and avocado, Ahlroth et al. investigated cross-reactive proteins between natural rubber latex and avocado in 1995 by using skin-prick tests with fresh avocado on 11 patients and the sera of 18 patients with known latex allergy for IgE antibodies. Fourteen of the 18 sera were found to have IgE antibodies binding to 17 distinct avocado proteins, with multiple immunoblot experiments and skin-prick test results (positive in 7 of 11 patients) revealing marked immunologic cross-reactivity between latex and avocado.⁸

In 1998, Chen et al. set out to identify the cross-sensitizing allergen between latex and avocado, with hevein suspected. The researchers looked at sera samples from 118 health care workers allergic to latex and 78 patients with spina bifida who were allergic to latex. They noted a robust correlation between the prevalence of seropositive IgE antibodies to avocado in the presence of hevein-specific IgE antibodies in both groups. All members in the spina bifida group and 91 (73%) of the health care workers had positive IgE antibodies to hevein and high IgE values to avocado. Additional results supported the conclusion that sensitization to avocado in the majority of people allergic to latex is engendered by IgE-binding epitopes found in hevein.⁹

A year later, Diaz-Perales et al. considered the potential relevance of chitinases and complex glycans as factors in the then newly described latex/food syndrome, particularly in avocado, banana, and chestnuts. The investigators culled extracts from 20 various plant foods as well as latex. In immunoblot inhibition assays, the primary allergen and class I chitinase in avocado, Prs a 1, and the latex extract potently or completely blocked IgE binding by these constituents. Polyclonal antibodies to chitinases and sera from patients with latex/fruit allergy responded to reactive proteins of about 30-45 kd (putative class I chitinases) in chestnut, cherimoya, kiwi, mango, papaya, passion fruit, tomato, and wheat flour extracts. The glycans complex was deemed to be irrelevant in latex/fruit cross-reactivity, but the researchers found the putative class I chitinases to be notable players in the latex/fruit syndrome.¹⁰

According to Wagner and Breitender, anywhere from 30%-50% of people with known latex allergy also evince a related hypersensitivity or allergy to various plant-derived foods, with avocado, banana, chestnut, kiwi, peach, tomato, potato, and bell pepper among the foods most frequently linked to latex/fruit syndrome. They summarize that several plant defense proteins have been shown to be involved in the syndrome, with the most prominent, class I chitinases with an N-terminal hevein-like domain, having been found to cross-react with hevein (Hev b 6.02), a major IgE-binding allergen for individuals allergic to latex. A beta-1,3-glucanase, a key latex allergen, has also shown cross-reactivity with proteins of bell pepper, and another significant latex allergen, Hev b 7, a patatin-like protein, cross-reacts with its analogous protein in potato.¹¹

Conclusion

It is unknown whether latex allergy precedes or follows food allergy.11 The latex/food syndrome itself merits attention as a significant source of hypersensitivity to natural cosmeceutical ingredients. Dermatologists should be aware of the lengthy list of cross-reacting plant-derived products, particularly when it comes to reviewing topical product ingredients with susceptible or allergic patients. Latex-allergic patients may react to these natural ingredients in food or when topically applied to the skin.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at [email protected].

References

1. Nutter AF. Br J Dermatol 1979 Nov;101(5):597-8.

2. Kelly KJ et al. J Allergy Clin Immunol Pract. 2017 Sep-Oct;5(5):1212-16.

3. Blanco C et al. Ann Allergy. 1994 Oct;73(4):309-14.

4. Beezhold DH et al. Clin Exp Allergy. 1996 Apr;26(4):416-22.

5. Brehler R et al. Allergy. 1997 Apr;52(4):404-10.

6. Mäkinen-Kiljunen S. J Allergy Clin Immunol. 1994 Jun;93(6):990-6.

7. Mikkola JH et al. J Allergy Clin Immunol. 1998 Dec;102(6 Pt 1):1005-12.

8. Ahlroth M et al. J Allergy Clin Immunol. 1995 Aug;96(2):167-73.

9. Chen Z et al. J Allergy Clin Immunol. 1998 Sep;102(3):476-81.

10. Diaz-Perales A et al. J Allergy Clin Immunol. 1999 Sep;104(3 Pt 1):681-7.

11. Wagner S et al. Biochem Soc Trans. 2002 Nov;30(Pt 6):935-40.

The progression, not just age of onset, of Huntington’s disease can be predicted by a measurable genetic factor, researchers have learned.

Huntington’s, an inherited neurodegenerative disease that affects motor function and cognition, is caused by an expansion of the CAG trinucleotide sequence on the huntingtin gene. Scientists have previously linked younger age at onset to a higher number of CAG repeats on the gene, but the association between these and the rate of progression after onset was poorly understood.

In research published online August 12 in JAMA Neurology, investigators linked the rate of progression – which, like age at onset, is highly variable in Huntington’s – to CAG repeat length. CAG repeat length was strongly associated with distinct patterns of brain damage, as well as clinical measures of cognitive and motor decline.

For their research, Douglas R. Langbehn, MD, PhD, of the University of Iowa, Iowa City, and colleagues used data from two longitudinal observational studies in gene carriers for Huntington’s and nonrelated controls. The researchers looked at data from 443 participants (56% female; mean age, 44.4 years) who were followed for a mean of 4 years, with more than 2,000 study visits across the multisite cohort. Neuropsychiatric testing and brain imaging were conducted annually, using composite scoring systems of the investigators’ design. These composite scores sought to be more sensitive by combining results from several validated clinical and imaging tests.

Age and speed of decline in total functional capacity tracked with more CAG repeats, the researchers found. For example, in people with 40 CAG repeats, the estimated mean age of initial motor-cognitive score change was 42.46 years; for those with 45 repeats, 26.65 years, and for people with 50 CAG repeats, 18.49 years. Higher repeats were seen significantly associated with accelerated, nonlinear decline on both clinical and brain-volume measures, except gray matter volume, according to principal component analyses conducted on the data.

“We derived a single summary measure capturing the motor-cognitive phenotype and showed that the accelerating progression of the phenotype with aging is highly CAG repeat length dependent (i.e., those with higher CAG decline earlier and faster). Contrary to some previous assertions, this CAG dependence continues well past the onset of clinical illness,” Dr. Langbehn and colleagues wrote in their analysis. “By characterizing these CAG repeat length–dependent disease trajectories, we provide insights into disease progression that may guide future therapeutic approaches and identify the most appropriate intervention ages to prevent clinical decline.”

Dr. Langbehn and colleagues acknowledged as a limitation of their study its likely exclusion of the sickest subjects because of the cohorts’ design. The CHDI Foundation funded the study. Of the 16 coauthors, 13 reported receiving funding from CHDI and/or from pharmaceutical manufacturers.

SOURCE: Langbehn et al. JAMA Neurol. 2019 Aug 12. doi: 10.1001/jamaneurol.2019.2328

The progression, not just age of onset, of Huntington’s disease can be predicted by a measurable genetic factor, researchers have learned.

Huntington’s, an inherited neurodegenerative disease that affects motor function and cognition, is caused by an expansion of the CAG trinucleotide sequence on the huntingtin gene. Scientists have previously linked younger age at onset to a higher number of CAG repeats on the gene, but the association between these and the rate of progression after onset was poorly understood.

In research published online August 12 in JAMA Neurology, investigators linked the rate of progression – which, like age at onset, is highly variable in Huntington’s – to CAG repeat length. CAG repeat length was strongly associated with distinct patterns of brain damage, as well as clinical measures of cognitive and motor decline.

For their research, Douglas R. Langbehn, MD, PhD, of the University of Iowa, Iowa City, and colleagues used data from two longitudinal observational studies in gene carriers for Huntington’s and nonrelated controls. The researchers looked at data from 443 participants (56% female; mean age, 44.4 years) who were followed for a mean of 4 years, with more than 2,000 study visits across the multisite cohort. Neuropsychiatric testing and brain imaging were conducted annually, using composite scoring systems of the investigators’ design. These composite scores sought to be more sensitive by combining results from several validated clinical and imaging tests.

Age and speed of decline in total functional capacity tracked with more CAG repeats, the researchers found. For example, in people with 40 CAG repeats, the estimated mean age of initial motor-cognitive score change was 42.46 years; for those with 45 repeats, 26.65 years, and for people with 50 CAG repeats, 18.49 years. Higher repeats were seen significantly associated with accelerated, nonlinear decline on both clinical and brain-volume measures, except gray matter volume, according to principal component analyses conducted on the data.

“We derived a single summary measure capturing the motor-cognitive phenotype and showed that the accelerating progression of the phenotype with aging is highly CAG repeat length dependent (i.e., those with higher CAG decline earlier and faster). Contrary to some previous assertions, this CAG dependence continues well past the onset of clinical illness,” Dr. Langbehn and colleagues wrote in their analysis. “By characterizing these CAG repeat length–dependent disease trajectories, we provide insights into disease progression that may guide future therapeutic approaches and identify the most appropriate intervention ages to prevent clinical decline.”

Dr. Langbehn and colleagues acknowledged as a limitation of their study its likely exclusion of the sickest subjects because of the cohorts’ design. The CHDI Foundation funded the study. Of the 16 coauthors, 13 reported receiving funding from CHDI and/or from pharmaceutical manufacturers.

SOURCE: Langbehn et al. JAMA Neurol. 2019 Aug 12. doi: 10.1001/jamaneurol.2019.2328

The progression, not just age of onset, of Huntington’s disease can be predicted by a measurable genetic factor, researchers have learned.

Huntington’s, an inherited neurodegenerative disease that affects motor function and cognition, is caused by an expansion of the CAG trinucleotide sequence on the huntingtin gene. Scientists have previously linked younger age at onset to a higher number of CAG repeats on the gene, but the association between these and the rate of progression after onset was poorly understood.

In research published online August 12 in JAMA Neurology, investigators linked the rate of progression – which, like age at onset, is highly variable in Huntington’s – to CAG repeat length. CAG repeat length was strongly associated with distinct patterns of brain damage, as well as clinical measures of cognitive and motor decline.

For their research, Douglas R. Langbehn, MD, PhD, of the University of Iowa, Iowa City, and colleagues used data from two longitudinal observational studies in gene carriers for Huntington’s and nonrelated controls. The researchers looked at data from 443 participants (56% female; mean age, 44.4 years) who were followed for a mean of 4 years, with more than 2,000 study visits across the multisite cohort. Neuropsychiatric testing and brain imaging were conducted annually, using composite scoring systems of the investigators’ design. These composite scores sought to be more sensitive by combining results from several validated clinical and imaging tests.

Age and speed of decline in total functional capacity tracked with more CAG repeats, the researchers found. For example, in people with 40 CAG repeats, the estimated mean age of initial motor-cognitive score change was 42.46 years; for those with 45 repeats, 26.65 years, and for people with 50 CAG repeats, 18.49 years. Higher repeats were seen significantly associated with accelerated, nonlinear decline on both clinical and brain-volume measures, except gray matter volume, according to principal component analyses conducted on the data.

“We derived a single summary measure capturing the motor-cognitive phenotype and showed that the accelerating progression of the phenotype with aging is highly CAG repeat length dependent (i.e., those with higher CAG decline earlier and faster). Contrary to some previous assertions, this CAG dependence continues well past the onset of clinical illness,” Dr. Langbehn and colleagues wrote in their analysis. “By characterizing these CAG repeat length–dependent disease trajectories, we provide insights into disease progression that may guide future therapeutic approaches and identify the most appropriate intervention ages to prevent clinical decline.”

Dr. Langbehn and colleagues acknowledged as a limitation of their study its likely exclusion of the sickest subjects because of the cohorts’ design. The CHDI Foundation funded the study. Of the 16 coauthors, 13 reported receiving funding from CHDI and/or from pharmaceutical manufacturers.

SOURCE: Langbehn et al. JAMA Neurol. 2019 Aug 12. doi: 10.1001/jamaneurol.2019.2328

Upadacitinib (Rinvoq) has been approved by the Food and Drug Administration for treatment of adults with moderately to severely active RA, according to a release from its developer. The indication specifies that patients must have shown inadequate response or intolerance to methotrexate.

The approval is based on the SELECT program, which included 4,400 patients across five studies that tested the oral Janus kinase inhibitor in various settings, such as alone or with methotrexate. All primary and secondary endpoints were met in these trials. For example, among patients with inadequate response to methotrexate in one study, 68% of those treated with 15-mg upadacitinib monotherapy achieved 20% improvement in American College of Rheumatology response criteria (ACR20) at week 14 versus 41% of those who had continued on methotrexate. In another study of patients with in adequate response to methotrexate, 71% of those treated with upadacitinib/methotrexate combination therapy achieved ACR20 at week 12 versus 36% of those receiving placebo and methotrexate. Compared with other treatments, better rates of clinical remission and radiographic inhibition were seen with upadacitinib-based therapies, too.

Upadacitinib carries a boxed warning – the most serious warning the FDA issues – for risks of serious infection, malignancy, and thrombosis; these serious risks should be weighed against treatment benefits in any patients with increased risk for these problems or currently experiencing any of them. Concomitant use with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants is not recommended; its use also is not recommended for patients with severe hepatic impairment. The most common adverse reactions are upper respiratory tract infection, nausea, cough, and pyrexia. Live vaccines should be avoided with patients taking this drug, and patients who are breastfeeding should be advised against use of it.

More prescribing information can be found in the drug’s label, which can be found on the FDA’s website.

Upadacitinib is also being evaluated for treatment of other immune-mediated diseases.

[email protected]

Upadacitinib (Rinvoq) has been approved by the Food and Drug Administration for treatment of adults with moderately to severely active RA, according to a release from its developer. The indication specifies that patients must have shown inadequate response or intolerance to methotrexate.

The approval is based on the SELECT program, which included 4,400 patients across five studies that tested the oral Janus kinase inhibitor in various settings, such as alone or with methotrexate. All primary and secondary endpoints were met in these trials. For example, among patients with inadequate response to methotrexate in one study, 68% of those treated with 15-mg upadacitinib monotherapy achieved 20% improvement in American College of Rheumatology response criteria (ACR20) at week 14 versus 41% of those who had continued on methotrexate. In another study of patients with in adequate response to methotrexate, 71% of those treated with upadacitinib/methotrexate combination therapy achieved ACR20 at week 12 versus 36% of those receiving placebo and methotrexate. Compared with other treatments, better rates of clinical remission and radiographic inhibition were seen with upadacitinib-based therapies, too.

Upadacitinib carries a boxed warning – the most serious warning the FDA issues – for risks of serious infection, malignancy, and thrombosis; these serious risks should be weighed against treatment benefits in any patients with increased risk for these problems or currently experiencing any of them. Concomitant use with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants is not recommended; its use also is not recommended for patients with severe hepatic impairment. The most common adverse reactions are upper respiratory tract infection, nausea, cough, and pyrexia. Live vaccines should be avoided with patients taking this drug, and patients who are breastfeeding should be advised against use of it.

More prescribing information can be found in the drug’s label, which can be found on the FDA’s website.

Upadacitinib is also being evaluated for treatment of other immune-mediated diseases.

[email protected]

Upadacitinib (Rinvoq) has been approved by the Food and Drug Administration for treatment of adults with moderately to severely active RA, according to a release from its developer. The indication specifies that patients must have shown inadequate response or intolerance to methotrexate.

The approval is based on the SELECT program, which included 4,400 patients across five studies that tested the oral Janus kinase inhibitor in various settings, such as alone or with methotrexate. All primary and secondary endpoints were met in these trials. For example, among patients with inadequate response to methotrexate in one study, 68% of those treated with 15-mg upadacitinib monotherapy achieved 20% improvement in American College of Rheumatology response criteria (ACR20) at week 14 versus 41% of those who had continued on methotrexate. In another study of patients with in adequate response to methotrexate, 71% of those treated with upadacitinib/methotrexate combination therapy achieved ACR20 at week 12 versus 36% of those receiving placebo and methotrexate. Compared with other treatments, better rates of clinical remission and radiographic inhibition were seen with upadacitinib-based therapies, too.

Upadacitinib carries a boxed warning – the most serious warning the FDA issues – for risks of serious infection, malignancy, and thrombosis; these serious risks should be weighed against treatment benefits in any patients with increased risk for these problems or currently experiencing any of them. Concomitant use with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants is not recommended; its use also is not recommended for patients with severe hepatic impairment. The most common adverse reactions are upper respiratory tract infection, nausea, cough, and pyrexia. Live vaccines should be avoided with patients taking this drug, and patients who are breastfeeding should be advised against use of it.

More prescribing information can be found in the drug’s label, which can be found on the FDA’s website.

Upadacitinib is also being evaluated for treatment of other immune-mediated diseases.

[email protected]

The EHR system at the hospital occasionally argues with me about my orders.

kokouu/iStockphoto

I may order a brain MRI, or CT angiography, or pretty much anything, and when I click to submit it a box pops up, telling me I shouldn’t be ordering that.

Sometimes it’s based on cost, saying that the MRI is more expensive than a CT, and according to some internal algorithm I should do that instead. Other times it says the test isn’t appropriate given the patient’s condition, age, zodiac sign, whatever. It might also say the test is redundant, because the patient just had a brain MRI during an admission last month.

I ignore them. There’s an override button to close the box and order the test, and that’s what I always click.

I have no objection to a reasonable review, but neither the computer nor its algorithms went through medical school, or residency, or read journals regularly, or have 20 years of experience in this field. I’d like to think (or hope) I know what I’m doing.

I don’t take this job lightly. When I order a test it’s because I’m trying to do the right thing for the patient. To find out what’s going on. To see what I can do to treat them. In short, to help as much as I can within the limitations of modern medical practice. Sometimes those things don’t always involve saving the insurance company money, or trying to get by with a previous study’s results.

Medicine is not a cookbook. While guidelines can be useful, every patient is different, and treatment plans have to be adjusted accordingly. It would be nice if this was the one-size-fits-all world the computer algorithms would like, but patient care is anything but.

I’d also rather “overcare” than “undercare.” To me, that’s just good practice. If I follow the computer’s advice and provide less care than needed and miss something, I’m pretty sure “because the computer told me not to” isn’t going to stand up as a defense in court.

I’m going to just keep on practicing medicine using, as one of my past attendings would say, “clinical correlation” and keeping what’s best for the patient in mind. Anything less may be fine for the computer, but not for me, and certainly not for those I’m trying to help.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

The EHR system at the hospital occasionally argues with me about my orders.

kokouu/iStockphoto

I may order a brain MRI, or CT angiography, or pretty much anything, and when I click to submit it a box pops up, telling me I shouldn’t be ordering that.

Sometimes it’s based on cost, saying that the MRI is more expensive than a CT, and according to some internal algorithm I should do that instead. Other times it says the test isn’t appropriate given the patient’s condition, age, zodiac sign, whatever. It might also say the test is redundant, because the patient just had a brain MRI during an admission last month.

I ignore them. There’s an override button to close the box and order the test, and that’s what I always click.

I have no objection to a reasonable review, but neither the computer nor its algorithms went through medical school, or residency, or read journals regularly, or have 20 years of experience in this field. I’d like to think (or hope) I know what I’m doing.

I don’t take this job lightly. When I order a test it’s because I’m trying to do the right thing for the patient. To find out what’s going on. To see what I can do to treat them. In short, to help as much as I can within the limitations of modern medical practice. Sometimes those things don’t always involve saving the insurance company money, or trying to get by with a previous study’s results.

Medicine is not a cookbook. While guidelines can be useful, every patient is different, and treatment plans have to be adjusted accordingly. It would be nice if this was the one-size-fits-all world the computer algorithms would like, but patient care is anything but.

I’d also rather “overcare” than “undercare.” To me, that’s just good practice. If I follow the computer’s advice and provide less care than needed and miss something, I’m pretty sure “because the computer told me not to” isn’t going to stand up as a defense in court.

I’m going to just keep on practicing medicine using, as one of my past attendings would say, “clinical correlation” and keeping what’s best for the patient in mind. Anything less may be fine for the computer, but not for me, and certainly not for those I’m trying to help.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

The EHR system at the hospital occasionally argues with me about my orders.

kokouu/iStockphoto

I may order a brain MRI, or CT angiography, or pretty much anything, and when I click to submit it a box pops up, telling me I shouldn’t be ordering that.

Sometimes it’s based on cost, saying that the MRI is more expensive than a CT, and according to some internal algorithm I should do that instead. Other times it says the test isn’t appropriate given the patient’s condition, age, zodiac sign, whatever. It might also say the test is redundant, because the patient just had a brain MRI during an admission last month.

I ignore them. There’s an override button to close the box and order the test, and that’s what I always click.

I have no objection to a reasonable review, but neither the computer nor its algorithms went through medical school, or residency, or read journals regularly, or have 20 years of experience in this field. I’d like to think (or hope) I know what I’m doing.

I don’t take this job lightly. When I order a test it’s because I’m trying to do the right thing for the patient. To find out what’s going on. To see what I can do to treat them. In short, to help as much as I can within the limitations of modern medical practice. Sometimes those things don’t always involve saving the insurance company money, or trying to get by with a previous study’s results.

Medicine is not a cookbook. While guidelines can be useful, every patient is different, and treatment plans have to be adjusted accordingly. It would be nice if this was the one-size-fits-all world the computer algorithms would like, but patient care is anything but.

I’d also rather “overcare” than “undercare.” To me, that’s just good practice. If I follow the computer’s advice and provide less care than needed and miss something, I’m pretty sure “because the computer told me not to” isn’t going to stand up as a defense in court.

I’m going to just keep on practicing medicine using, as one of my past attendings would say, “clinical correlation” and keeping what’s best for the patient in mind. Anything less may be fine for the computer, but not for me, and certainly not for those I’m trying to help.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.