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Think methotrexate for granulomatous mastitis
MAUI, HAWAII – Methotrexate is the most effective therapy for granulomatous mastitis, according to Anna Postolova, MD, a rheumatology fellow at Stanford (Calif.) University.
Granulomatous mastitis is a rare inflammatory disease of the breast of uncertain but possibly autoimmune etiology. The most common treatments – antibiotics, prednisone, and incision and drainage – are often ineffective and have a roughly 50% recurrence rate. That’s why Stanford rheumatologists began using methotrexate more than a decade ago with impressive results, she explained at the 2018 Rheumatology Winter Clinical Symposium.
Dr. Postolova presented a retrospective series of 19 women referred to Stanford for recurrent or refractory granulomatous mastitis. At diagnosis, they averaged 33.5 years of age with a 6-month history of symptoms prior to diagnosis. Of the 19 women, 11 were Hispanic, and only 2 were Caucasian. A total of 17 women were multiparous, with an average of two children, and 3 women were breastfeeding at symptom onset.
The women were placed on methotrexate at 15 mg/week. At 3 months, 17 of the 19 patients showed improvement, but none had disease resolution. At that point the dose was raised to 20 mg/week. After 3 months at the higher dose, 16 of 18 patients were improved and 4 had experienced resolution of their granulomatous mastitis. After 9 months on methotrexate – 6 at the higher dose – the granulomatous mastitis showed continued improvement in 13 of 15 women and resolution in 8. One woman experienced recurrent disease at 9 months of follow-up after her methotrexate was withheld because of liver test abnormalities and lack of birth control; however, she went into remission upon restarting therapy.
By 12 months, 12 of 15 women, or 80%, had experienced disease resolution. Their methotrexate was then slowly tapered over the course of 18-24 months without disease recurrence.
On the other hand, two women who had previously shown improvement were experiencing mild recurrences at the 12-month mark. They were switched to subcutaneous methotrexate. One responded favorably to the change, and the other had not yet returned for follow-up.
Dr. Postolova reported having no financial conflicts of interest regarding her presentation.
MAUI, HAWAII – Methotrexate is the most effective therapy for granulomatous mastitis, according to Anna Postolova, MD, a rheumatology fellow at Stanford (Calif.) University.
Granulomatous mastitis is a rare inflammatory disease of the breast of uncertain but possibly autoimmune etiology. The most common treatments – antibiotics, prednisone, and incision and drainage – are often ineffective and have a roughly 50% recurrence rate. That’s why Stanford rheumatologists began using methotrexate more than a decade ago with impressive results, she explained at the 2018 Rheumatology Winter Clinical Symposium.
Dr. Postolova presented a retrospective series of 19 women referred to Stanford for recurrent or refractory granulomatous mastitis. At diagnosis, they averaged 33.5 years of age with a 6-month history of symptoms prior to diagnosis. Of the 19 women, 11 were Hispanic, and only 2 were Caucasian. A total of 17 women were multiparous, with an average of two children, and 3 women were breastfeeding at symptom onset.
The women were placed on methotrexate at 15 mg/week. At 3 months, 17 of the 19 patients showed improvement, but none had disease resolution. At that point the dose was raised to 20 mg/week. After 3 months at the higher dose, 16 of 18 patients were improved and 4 had experienced resolution of their granulomatous mastitis. After 9 months on methotrexate – 6 at the higher dose – the granulomatous mastitis showed continued improvement in 13 of 15 women and resolution in 8. One woman experienced recurrent disease at 9 months of follow-up after her methotrexate was withheld because of liver test abnormalities and lack of birth control; however, she went into remission upon restarting therapy.
By 12 months, 12 of 15 women, or 80%, had experienced disease resolution. Their methotrexate was then slowly tapered over the course of 18-24 months without disease recurrence.
On the other hand, two women who had previously shown improvement were experiencing mild recurrences at the 12-month mark. They were switched to subcutaneous methotrexate. One responded favorably to the change, and the other had not yet returned for follow-up.
Dr. Postolova reported having no financial conflicts of interest regarding her presentation.
MAUI, HAWAII – Methotrexate is the most effective therapy for granulomatous mastitis, according to Anna Postolova, MD, a rheumatology fellow at Stanford (Calif.) University.
Granulomatous mastitis is a rare inflammatory disease of the breast of uncertain but possibly autoimmune etiology. The most common treatments – antibiotics, prednisone, and incision and drainage – are often ineffective and have a roughly 50% recurrence rate. That’s why Stanford rheumatologists began using methotrexate more than a decade ago with impressive results, she explained at the 2018 Rheumatology Winter Clinical Symposium.
Dr. Postolova presented a retrospective series of 19 women referred to Stanford for recurrent or refractory granulomatous mastitis. At diagnosis, they averaged 33.5 years of age with a 6-month history of symptoms prior to diagnosis. Of the 19 women, 11 were Hispanic, and only 2 were Caucasian. A total of 17 women were multiparous, with an average of two children, and 3 women were breastfeeding at symptom onset.
The women were placed on methotrexate at 15 mg/week. At 3 months, 17 of the 19 patients showed improvement, but none had disease resolution. At that point the dose was raised to 20 mg/week. After 3 months at the higher dose, 16 of 18 patients were improved and 4 had experienced resolution of their granulomatous mastitis. After 9 months on methotrexate – 6 at the higher dose – the granulomatous mastitis showed continued improvement in 13 of 15 women and resolution in 8. One woman experienced recurrent disease at 9 months of follow-up after her methotrexate was withheld because of liver test abnormalities and lack of birth control; however, she went into remission upon restarting therapy.
By 12 months, 12 of 15 women, or 80%, had experienced disease resolution. Their methotrexate was then slowly tapered over the course of 18-24 months without disease recurrence.
On the other hand, two women who had previously shown improvement were experiencing mild recurrences at the 12-month mark. They were switched to subcutaneous methotrexate. One responded favorably to the change, and the other had not yet returned for follow-up.
Dr. Postolova reported having no financial conflicts of interest regarding her presentation.
EXPERT ANALYSIS FROM RWCS 2018
Key clinical point:
Major finding: At 3 months, 17 of 19 patients showed improvement on methotrexate at 15 mg/week, and at 12 months, 12 of 15 had experienced disease resolution on 20 mg/week.
Study details: A single-center retrospective review of 19 patients with granulomatous mastitis.
Disclosures: The presenter reported having no financial conflicts of interest regarding her presentation.
Tardive dyskinesia is theme of awards competition for early career psychiatrists
Important advances in neuroscience and clinical psychiatry have been achieved in recent years, but there are significant gaps in knowledge and much that we don’t understand about the brain and behavior. Further advances depend on cultivating and supporting a new generation of dedicated basic science and clinical investigators. While there is a compelling need to attract, recruit, and encourage talented individuals to pursue scholarly interests, competing life and career demands often prove daunting.
The theme of the competition this year concerning tardive dyskinesia is timely and consistent with the mission of NMSIS to promote knowledge on neurologic side effects of antipsychotic drugs. Tardive dyskinesia can have a negative impact on the social, psychological, and physical well-being of patients; it remains a legacy of past treatment with antipsychotics; it is an increasing concern among an ever widening population of patients receiving even newer antipsychotics; and there are now two Food and Drug Administration–approved treatments for the disorder. Early career psychiatrists may have had limited instruction on tardive dyskinesia, which has not received prominent attention in curricular programs in recent years. Thus, in addition to supporting scholarly work and research experience, the 2018 Promising Scholars Award Program aims to promote knowledge and skills in managing patients with tardive dyskinesia.
Specific learning objectives are:
- Participants will learn the steps necessary to prepare a scientific manuscript for publication.
- Participants will review comments by expert referees and learn to incorporate and respond to the peer review process.
- Participants will review the evidence related to the diagnosis and treatment of tardive dyskinesia.
- Participants will be introduced to the spectrum of educational and networking opportunities at the Institute for Psychiatric Services conference.
In the past, this program was very popular and gained national recognition among psychiatric trainees. Numerous submitted papers were accepted for publication in peer-reviewed journals after the competition was completed.
Instructions for manuscript preparation are:
- First author must be a student, resident, or fellow.
- Papers should address specific issues related to the theme of tardive dyskinesia and be no longer than 15 double-spaced typed pages in length (excluding references and illustrations).
- Literature reviews, case reports, or studies that are original and newly developed or recently published are acceptable.
- Reviews and feedback will be provided by a panel of academic psychiatrists.
- Papers will be judged on relevance to tardive dyskinesia, originality, scholarship, scientific rigor, valid methodology, clinical significance, and organization.
To participate, papers and curriculum vitae of the first author must be submitted by July 1, 2018, to Dianne Daugherty by email at dianne@mhaus.org. Winners will be announced by Aug. 10, 2018. For additional information, write to dianne@mhaus.org or visit www.mhaus.org/nmsis/about-us/what-is-nmsis.
Dr. Caroff, professor of psychiatry, Corporal Michael J. Crescenz VA Medical Center and at the University of Pennsylvania, both in Philadelphia, is director of the NMSIS. He served as consultant to Neurocrine Biosciences and Teva Pharmaceutical Industries, and receives research grant funding from Neurocrine Biosciences.
Important advances in neuroscience and clinical psychiatry have been achieved in recent years, but there are significant gaps in knowledge and much that we don’t understand about the brain and behavior. Further advances depend on cultivating and supporting a new generation of dedicated basic science and clinical investigators. While there is a compelling need to attract, recruit, and encourage talented individuals to pursue scholarly interests, competing life and career demands often prove daunting.
The theme of the competition this year concerning tardive dyskinesia is timely and consistent with the mission of NMSIS to promote knowledge on neurologic side effects of antipsychotic drugs. Tardive dyskinesia can have a negative impact on the social, psychological, and physical well-being of patients; it remains a legacy of past treatment with antipsychotics; it is an increasing concern among an ever widening population of patients receiving even newer antipsychotics; and there are now two Food and Drug Administration–approved treatments for the disorder. Early career psychiatrists may have had limited instruction on tardive dyskinesia, which has not received prominent attention in curricular programs in recent years. Thus, in addition to supporting scholarly work and research experience, the 2018 Promising Scholars Award Program aims to promote knowledge and skills in managing patients with tardive dyskinesia.
Specific learning objectives are:
- Participants will learn the steps necessary to prepare a scientific manuscript for publication.
- Participants will review comments by expert referees and learn to incorporate and respond to the peer review process.
- Participants will review the evidence related to the diagnosis and treatment of tardive dyskinesia.
- Participants will be introduced to the spectrum of educational and networking opportunities at the Institute for Psychiatric Services conference.
In the past, this program was very popular and gained national recognition among psychiatric trainees. Numerous submitted papers were accepted for publication in peer-reviewed journals after the competition was completed.
Instructions for manuscript preparation are:
- First author must be a student, resident, or fellow.
- Papers should address specific issues related to the theme of tardive dyskinesia and be no longer than 15 double-spaced typed pages in length (excluding references and illustrations).
- Literature reviews, case reports, or studies that are original and newly developed or recently published are acceptable.
- Reviews and feedback will be provided by a panel of academic psychiatrists.
- Papers will be judged on relevance to tardive dyskinesia, originality, scholarship, scientific rigor, valid methodology, clinical significance, and organization.
To participate, papers and curriculum vitae of the first author must be submitted by July 1, 2018, to Dianne Daugherty by email at dianne@mhaus.org. Winners will be announced by Aug. 10, 2018. For additional information, write to dianne@mhaus.org or visit www.mhaus.org/nmsis/about-us/what-is-nmsis.
Dr. Caroff, professor of psychiatry, Corporal Michael J. Crescenz VA Medical Center and at the University of Pennsylvania, both in Philadelphia, is director of the NMSIS. He served as consultant to Neurocrine Biosciences and Teva Pharmaceutical Industries, and receives research grant funding from Neurocrine Biosciences.
Important advances in neuroscience and clinical psychiatry have been achieved in recent years, but there are significant gaps in knowledge and much that we don’t understand about the brain and behavior. Further advances depend on cultivating and supporting a new generation of dedicated basic science and clinical investigators. While there is a compelling need to attract, recruit, and encourage talented individuals to pursue scholarly interests, competing life and career demands often prove daunting.
The theme of the competition this year concerning tardive dyskinesia is timely and consistent with the mission of NMSIS to promote knowledge on neurologic side effects of antipsychotic drugs. Tardive dyskinesia can have a negative impact on the social, psychological, and physical well-being of patients; it remains a legacy of past treatment with antipsychotics; it is an increasing concern among an ever widening population of patients receiving even newer antipsychotics; and there are now two Food and Drug Administration–approved treatments for the disorder. Early career psychiatrists may have had limited instruction on tardive dyskinesia, which has not received prominent attention in curricular programs in recent years. Thus, in addition to supporting scholarly work and research experience, the 2018 Promising Scholars Award Program aims to promote knowledge and skills in managing patients with tardive dyskinesia.
Specific learning objectives are:
- Participants will learn the steps necessary to prepare a scientific manuscript for publication.
- Participants will review comments by expert referees and learn to incorporate and respond to the peer review process.
- Participants will review the evidence related to the diagnosis and treatment of tardive dyskinesia.
- Participants will be introduced to the spectrum of educational and networking opportunities at the Institute for Psychiatric Services conference.
In the past, this program was very popular and gained national recognition among psychiatric trainees. Numerous submitted papers were accepted for publication in peer-reviewed journals after the competition was completed.
Instructions for manuscript preparation are:
- First author must be a student, resident, or fellow.
- Papers should address specific issues related to the theme of tardive dyskinesia and be no longer than 15 double-spaced typed pages in length (excluding references and illustrations).
- Literature reviews, case reports, or studies that are original and newly developed or recently published are acceptable.
- Reviews and feedback will be provided by a panel of academic psychiatrists.
- Papers will be judged on relevance to tardive dyskinesia, originality, scholarship, scientific rigor, valid methodology, clinical significance, and organization.
To participate, papers and curriculum vitae of the first author must be submitted by July 1, 2018, to Dianne Daugherty by email at dianne@mhaus.org. Winners will be announced by Aug. 10, 2018. For additional information, write to dianne@mhaus.org or visit www.mhaus.org/nmsis/about-us/what-is-nmsis.
Dr. Caroff, professor of psychiatry, Corporal Michael J. Crescenz VA Medical Center and at the University of Pennsylvania, both in Philadelphia, is director of the NMSIS. He served as consultant to Neurocrine Biosciences and Teva Pharmaceutical Industries, and receives research grant funding from Neurocrine Biosciences.
A Recalcitrant Case of Toxic Epidermal Necrolysis
One of the most severe complications of systemic medications is the development of a life-threatening rash, especially toxic epidermal necrolysis (TEN). Most patients can expect a full recovery if the complicating medication is discontinued early on in its course.1 When suspected TEN does not improve despite discontinuation of the detrimental medication, other diseases must be considered, particularly immunobullous and infectious etiologies. Treatment of these diseases differs substantially; therefore, a quick diagnosis is crucial. We present a case of a patient with an acute blistering eruption that was initially diagnosed and managed as TEN but physical examination and histopathologic confirmed another diagnosis. We review key examination findings that can help differentiate the causes of an acute blistering eruption with mucosal involvement, allowing for earlier diagnosis and treatment of these patients.
Case Report
An 85-year-old immunocompetent man was admitted to an outside hospital with a pruritic blistering eruption associated with myalgia, weakness, and fatigue of 3 weeks’ duration. The eruption initiated on the scalp and face and then spread down to the trunk and proximal arms and legs, with oral erosions also reported. An outside dermatologist was consulted on admission and performed a skin biopsy; the initial pathology was read as TEN. The patient was admitted to our institution on the same day, and all potentially complicating medications were stopped. He was treated with intravenous (IV)
At that time, physical examination revealed numerous confluent erosions with honey-colored crust involving the entire face (Figure 1A) and sharp demarcation at the cutaneous lip (Figure 1B). There was a large erosion on the dorsal aspect of the tongue, but the rest of the oral mucosa was spared. The trunk and proximal extremities showed numerous grouped, punched-out erosions with scalloped borders (Figure 1C). A repeat skin biopsy showed an ulcer with viral cytopathic changes. Immunoperoxidase studies demonstrated positive staining for herpes simplex virus (HSV) type 1 (Figure 2). The original slides were a frozen section from an outside facility and could not be obtained. A tissue culture and direct fluorescent antibody also confirmed HSV-1, and the patient was diagnosed with disseminated herpes. He was rapidly tapered off of the steroids and started on IV acyclovir 10 mg/kg every 8 hours for 21 days. All prior erosions reepithelialized within 7 days of treatment (Figure 3). The patient had an otherwise uncomplicated hospital course and was discharged on hospital day 21.
Comment
A patient with an acute generalized blistering eruption requires urgent workup and treatment given the potentially devastating sequelae. Toxic epidermal necrolysis and immunobullous diseases often are the first diagnoses to be ruled out. Certainly infections such as HSV can cause a vesicular and erosive eruption, especially in the setting of a poorly controlled dermatitis, but they typically are not in the same differential as the other diagnoses.
Clinical Presentation
This case highlights 2 key physical examination findings that can alert the clinician to a possible underlying herpetic infection. First, the distribution of this patient’s oral lesions was telling. In most cases of TEN or pemphigus vulgaris, there is notable involvement of the oral mucosa, particularly the buccal and labial mucosa. Although herpes can involve any mucocutaneous surface, it does have a predilection for keratinized tissue, with the tongue and cutaneous lip commonly involved.2,3 Our patient had a solitary linear erosion on the dorsal aspect of the tongue, but the rest of the oral cavity was strikingly spared. In addition, the erosions around the mouth stopped right at the cutaneous lip, sparing the labial mucosa (Figure 1B).
Second, the configuration of the erosions on the trunk, arms, and legs was diagnostic. Herpes classically presents as a cluster of vesicles overlying an erythematous base. When these vesicles rupture, punched-out erosions are left behind. Because these vesicles often are grouped, they can develop a scalloped border, which is a helpful indicator of HSV (Figure 1C). When these erosions become more confluent and irregular, the distinction from other conditions may not be as clear. A careful skin examination often can show areas that have preserved this herpetiform configuration.
Immune Compromise
Additionally, this case is illustrative of how immunosuppression and immunocompromise can affect the clinical presentation of HSV infection. Herpetic infections in the immunocompromised host tend to have a more protracted course, with chronic enlarging ulcers involving multiple sites.
Conclusion
This case is a good reminder that not everything that blisters and involves the mucosa is due to a hypersensitivity state such as TEN and Stevens-Johnson syndrome or an immunobullous disorder such as pemphigus vulgaris and pemphigus vegetans. The fact that this patient was worsening despite drug cessation, high-dose steroids, and IV immunoglobulin should have indicated a misdiagnosis. This case also shows that the early histopathologic findings of disseminated HSV and TEN can be nonspecific, and viral cytopathic changes may not always be obvious early in the disease.
Disseminated HSV should be considered in the differential diagnosis of a patient with an acute blistering eruption with mucosal involvement, and careful history and physical examination should be taken to rule out a viral etiology.
- Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: part I. introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol. 2013;69:173.e1-173.e13.
- Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. New York, NY: Mosby; 2008.
- Woo SB, Lee SF. Oral recrudescent herpes simplex virus infection. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83:239-243.
One of the most severe complications of systemic medications is the development of a life-threatening rash, especially toxic epidermal necrolysis (TEN). Most patients can expect a full recovery if the complicating medication is discontinued early on in its course.1 When suspected TEN does not improve despite discontinuation of the detrimental medication, other diseases must be considered, particularly immunobullous and infectious etiologies. Treatment of these diseases differs substantially; therefore, a quick diagnosis is crucial. We present a case of a patient with an acute blistering eruption that was initially diagnosed and managed as TEN but physical examination and histopathologic confirmed another diagnosis. We review key examination findings that can help differentiate the causes of an acute blistering eruption with mucosal involvement, allowing for earlier diagnosis and treatment of these patients.
Case Report
An 85-year-old immunocompetent man was admitted to an outside hospital with a pruritic blistering eruption associated with myalgia, weakness, and fatigue of 3 weeks’ duration. The eruption initiated on the scalp and face and then spread down to the trunk and proximal arms and legs, with oral erosions also reported. An outside dermatologist was consulted on admission and performed a skin biopsy; the initial pathology was read as TEN. The patient was admitted to our institution on the same day, and all potentially complicating medications were stopped. He was treated with intravenous (IV)
At that time, physical examination revealed numerous confluent erosions with honey-colored crust involving the entire face (Figure 1A) and sharp demarcation at the cutaneous lip (Figure 1B). There was a large erosion on the dorsal aspect of the tongue, but the rest of the oral mucosa was spared. The trunk and proximal extremities showed numerous grouped, punched-out erosions with scalloped borders (Figure 1C). A repeat skin biopsy showed an ulcer with viral cytopathic changes. Immunoperoxidase studies demonstrated positive staining for herpes simplex virus (HSV) type 1 (Figure 2). The original slides were a frozen section from an outside facility and could not be obtained. A tissue culture and direct fluorescent antibody also confirmed HSV-1, and the patient was diagnosed with disseminated herpes. He was rapidly tapered off of the steroids and started on IV acyclovir 10 mg/kg every 8 hours for 21 days. All prior erosions reepithelialized within 7 days of treatment (Figure 3). The patient had an otherwise uncomplicated hospital course and was discharged on hospital day 21.
Comment
A patient with an acute generalized blistering eruption requires urgent workup and treatment given the potentially devastating sequelae. Toxic epidermal necrolysis and immunobullous diseases often are the first diagnoses to be ruled out. Certainly infections such as HSV can cause a vesicular and erosive eruption, especially in the setting of a poorly controlled dermatitis, but they typically are not in the same differential as the other diagnoses.
Clinical Presentation
This case highlights 2 key physical examination findings that can alert the clinician to a possible underlying herpetic infection. First, the distribution of this patient’s oral lesions was telling. In most cases of TEN or pemphigus vulgaris, there is notable involvement of the oral mucosa, particularly the buccal and labial mucosa. Although herpes can involve any mucocutaneous surface, it does have a predilection for keratinized tissue, with the tongue and cutaneous lip commonly involved.2,3 Our patient had a solitary linear erosion on the dorsal aspect of the tongue, but the rest of the oral cavity was strikingly spared. In addition, the erosions around the mouth stopped right at the cutaneous lip, sparing the labial mucosa (Figure 1B).
Second, the configuration of the erosions on the trunk, arms, and legs was diagnostic. Herpes classically presents as a cluster of vesicles overlying an erythematous base. When these vesicles rupture, punched-out erosions are left behind. Because these vesicles often are grouped, they can develop a scalloped border, which is a helpful indicator of HSV (Figure 1C). When these erosions become more confluent and irregular, the distinction from other conditions may not be as clear. A careful skin examination often can show areas that have preserved this herpetiform configuration.
Immune Compromise
Additionally, this case is illustrative of how immunosuppression and immunocompromise can affect the clinical presentation of HSV infection. Herpetic infections in the immunocompromised host tend to have a more protracted course, with chronic enlarging ulcers involving multiple sites.
Conclusion
This case is a good reminder that not everything that blisters and involves the mucosa is due to a hypersensitivity state such as TEN and Stevens-Johnson syndrome or an immunobullous disorder such as pemphigus vulgaris and pemphigus vegetans. The fact that this patient was worsening despite drug cessation, high-dose steroids, and IV immunoglobulin should have indicated a misdiagnosis. This case also shows that the early histopathologic findings of disseminated HSV and TEN can be nonspecific, and viral cytopathic changes may not always be obvious early in the disease.
Disseminated HSV should be considered in the differential diagnosis of a patient with an acute blistering eruption with mucosal involvement, and careful history and physical examination should be taken to rule out a viral etiology.
One of the most severe complications of systemic medications is the development of a life-threatening rash, especially toxic epidermal necrolysis (TEN). Most patients can expect a full recovery if the complicating medication is discontinued early on in its course.1 When suspected TEN does not improve despite discontinuation of the detrimental medication, other diseases must be considered, particularly immunobullous and infectious etiologies. Treatment of these diseases differs substantially; therefore, a quick diagnosis is crucial. We present a case of a patient with an acute blistering eruption that was initially diagnosed and managed as TEN but physical examination and histopathologic confirmed another diagnosis. We review key examination findings that can help differentiate the causes of an acute blistering eruption with mucosal involvement, allowing for earlier diagnosis and treatment of these patients.
Case Report
An 85-year-old immunocompetent man was admitted to an outside hospital with a pruritic blistering eruption associated with myalgia, weakness, and fatigue of 3 weeks’ duration. The eruption initiated on the scalp and face and then spread down to the trunk and proximal arms and legs, with oral erosions also reported. An outside dermatologist was consulted on admission and performed a skin biopsy; the initial pathology was read as TEN. The patient was admitted to our institution on the same day, and all potentially complicating medications were stopped. He was treated with intravenous (IV)
At that time, physical examination revealed numerous confluent erosions with honey-colored crust involving the entire face (Figure 1A) and sharp demarcation at the cutaneous lip (Figure 1B). There was a large erosion on the dorsal aspect of the tongue, but the rest of the oral mucosa was spared. The trunk and proximal extremities showed numerous grouped, punched-out erosions with scalloped borders (Figure 1C). A repeat skin biopsy showed an ulcer with viral cytopathic changes. Immunoperoxidase studies demonstrated positive staining for herpes simplex virus (HSV) type 1 (Figure 2). The original slides were a frozen section from an outside facility and could not be obtained. A tissue culture and direct fluorescent antibody also confirmed HSV-1, and the patient was diagnosed with disseminated herpes. He was rapidly tapered off of the steroids and started on IV acyclovir 10 mg/kg every 8 hours for 21 days. All prior erosions reepithelialized within 7 days of treatment (Figure 3). The patient had an otherwise uncomplicated hospital course and was discharged on hospital day 21.
Comment
A patient with an acute generalized blistering eruption requires urgent workup and treatment given the potentially devastating sequelae. Toxic epidermal necrolysis and immunobullous diseases often are the first diagnoses to be ruled out. Certainly infections such as HSV can cause a vesicular and erosive eruption, especially in the setting of a poorly controlled dermatitis, but they typically are not in the same differential as the other diagnoses.
Clinical Presentation
This case highlights 2 key physical examination findings that can alert the clinician to a possible underlying herpetic infection. First, the distribution of this patient’s oral lesions was telling. In most cases of TEN or pemphigus vulgaris, there is notable involvement of the oral mucosa, particularly the buccal and labial mucosa. Although herpes can involve any mucocutaneous surface, it does have a predilection for keratinized tissue, with the tongue and cutaneous lip commonly involved.2,3 Our patient had a solitary linear erosion on the dorsal aspect of the tongue, but the rest of the oral cavity was strikingly spared. In addition, the erosions around the mouth stopped right at the cutaneous lip, sparing the labial mucosa (Figure 1B).
Second, the configuration of the erosions on the trunk, arms, and legs was diagnostic. Herpes classically presents as a cluster of vesicles overlying an erythematous base. When these vesicles rupture, punched-out erosions are left behind. Because these vesicles often are grouped, they can develop a scalloped border, which is a helpful indicator of HSV (Figure 1C). When these erosions become more confluent and irregular, the distinction from other conditions may not be as clear. A careful skin examination often can show areas that have preserved this herpetiform configuration.
Immune Compromise
Additionally, this case is illustrative of how immunosuppression and immunocompromise can affect the clinical presentation of HSV infection. Herpetic infections in the immunocompromised host tend to have a more protracted course, with chronic enlarging ulcers involving multiple sites.
Conclusion
This case is a good reminder that not everything that blisters and involves the mucosa is due to a hypersensitivity state such as TEN and Stevens-Johnson syndrome or an immunobullous disorder such as pemphigus vulgaris and pemphigus vegetans. The fact that this patient was worsening despite drug cessation, high-dose steroids, and IV immunoglobulin should have indicated a misdiagnosis. This case also shows that the early histopathologic findings of disseminated HSV and TEN can be nonspecific, and viral cytopathic changes may not always be obvious early in the disease.
Disseminated HSV should be considered in the differential diagnosis of a patient with an acute blistering eruption with mucosal involvement, and careful history and physical examination should be taken to rule out a viral etiology.
- Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: part I. introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol. 2013;69:173.e1-173.e13.
- Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. New York, NY: Mosby; 2008.
- Woo SB, Lee SF. Oral recrudescent herpes simplex virus infection. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83:239-243.
- Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: part I. introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol. 2013;69:173.e1-173.e13.
- Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. New York, NY: Mosby; 2008.
- Woo SB, Lee SF. Oral recrudescent herpes simplex virus infection. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83:239-243.
Practice Points
- Toxic epidermal necrolysis can be difficult to diagnose and treat.
- Patients who are refractory to treatment should prompt further management considerations.
The retirement horizon creeps up
My lease is up later this year, after 5 1/2 years. It doesn’t seem that long. Some days it feels like I just moved in.
As a result, I had an email exchange recently with the building’s manager and we hashed out an agreement on a new 10-year contract. In the process, I realized that sort of time frame might (and, again, I say might) take me into retirement.
And now I’m starting to think about retiring and the career endgame.
Granted, it’s still 10 years away, and knowing me I’ll probably want to work another 5 years or so beyond that if I can. I like what I do and would probably go stir crazy without this job. Besides, given the current anti-doctor financial climate, I may not be able to retire in 10 years, even if I want to.
But still, it’s an odd realization to think that, after all those applications, and classes, and tests, and rotations, and all the other things you went through ... that your career is closer to wrapping up than it is to the beginning.
How did that happen?
And I’ll continue to try. Even after the halfway point I still get up each morning wanting to help people. The same sentiments I expressed in a personal statement so long ago are still there, and hopefully always will be. When they’re gone, it’s time to leave. Hopefully, they’ll be with me until I’m ready to sign off.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
My lease is up later this year, after 5 1/2 years. It doesn’t seem that long. Some days it feels like I just moved in.
As a result, I had an email exchange recently with the building’s manager and we hashed out an agreement on a new 10-year contract. In the process, I realized that sort of time frame might (and, again, I say might) take me into retirement.
And now I’m starting to think about retiring and the career endgame.
Granted, it’s still 10 years away, and knowing me I’ll probably want to work another 5 years or so beyond that if I can. I like what I do and would probably go stir crazy without this job. Besides, given the current anti-doctor financial climate, I may not be able to retire in 10 years, even if I want to.
But still, it’s an odd realization to think that, after all those applications, and classes, and tests, and rotations, and all the other things you went through ... that your career is closer to wrapping up than it is to the beginning.
How did that happen?
And I’ll continue to try. Even after the halfway point I still get up each morning wanting to help people. The same sentiments I expressed in a personal statement so long ago are still there, and hopefully always will be. When they’re gone, it’s time to leave. Hopefully, they’ll be with me until I’m ready to sign off.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
My lease is up later this year, after 5 1/2 years. It doesn’t seem that long. Some days it feels like I just moved in.
As a result, I had an email exchange recently with the building’s manager and we hashed out an agreement on a new 10-year contract. In the process, I realized that sort of time frame might (and, again, I say might) take me into retirement.
And now I’m starting to think about retiring and the career endgame.
Granted, it’s still 10 years away, and knowing me I’ll probably want to work another 5 years or so beyond that if I can. I like what I do and would probably go stir crazy without this job. Besides, given the current anti-doctor financial climate, I may not be able to retire in 10 years, even if I want to.
But still, it’s an odd realization to think that, after all those applications, and classes, and tests, and rotations, and all the other things you went through ... that your career is closer to wrapping up than it is to the beginning.
How did that happen?
And I’ll continue to try. Even after the halfway point I still get up each morning wanting to help people. The same sentiments I expressed in a personal statement so long ago are still there, and hopefully always will be. When they’re gone, it’s time to leave. Hopefully, they’ll be with me until I’m ready to sign off.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
FDA updates breast implant–associated lymphoma cases, risk
(BIA-ALCL), including nine deaths.
This figure includes all medical device reports received by the agency between 2011 and September 2017. The FDA recently provided an update on ALCL linked to breast implants and an estimate of lifetime risk of developing ALCL.
Based on available medical literature, the lifetime risk of developing BIA-ALCL for patients with textured breast implants ranges from 1 in 3,817 to 1 in 30,000, according to the update.
Of the 272 reports with data on surface type, 242 were textured implants and 30 were smooth implants. In addition, 413 reports include information on the implant fill type: 234 used silicone gel and 179 were saline filled.
“The FDA has been closely tracking the relationship between breast implants and a rare type of non-Hodgkin’s lymphoma since we first identified this possible association. We’ve been working to gather additional information to better characterize and quantify the risk so that patients and providers can have more informed discussions about breast implants,” said Binita Ashar, MD, director of the division of surgical devices in the FDA’s Center for Devices and Radiological Health. “As part of that effort, we are working to update and enhance the information we have on this association, including updating the total number of known cases of BIA-ALCL and the lifetime risk of developing BIA-ALCL as reported in medical literature.”
The possible association between breast implants and the development of anaplastic large cell lymphoma (ALCL) was first identified in 2011. At that time, there were not enough cases of to determine what factors increased a patient’s risk of developing the disease. As more information became available, the World Health Organization designated BIA-ALCL as a T-cell lymphoma that can develop following breast implants.
(BIA-ALCL), including nine deaths.
This figure includes all medical device reports received by the agency between 2011 and September 2017. The FDA recently provided an update on ALCL linked to breast implants and an estimate of lifetime risk of developing ALCL.
Based on available medical literature, the lifetime risk of developing BIA-ALCL for patients with textured breast implants ranges from 1 in 3,817 to 1 in 30,000, according to the update.
Of the 272 reports with data on surface type, 242 were textured implants and 30 were smooth implants. In addition, 413 reports include information on the implant fill type: 234 used silicone gel and 179 were saline filled.
“The FDA has been closely tracking the relationship between breast implants and a rare type of non-Hodgkin’s lymphoma since we first identified this possible association. We’ve been working to gather additional information to better characterize and quantify the risk so that patients and providers can have more informed discussions about breast implants,” said Binita Ashar, MD, director of the division of surgical devices in the FDA’s Center for Devices and Radiological Health. “As part of that effort, we are working to update and enhance the information we have on this association, including updating the total number of known cases of BIA-ALCL and the lifetime risk of developing BIA-ALCL as reported in medical literature.”
The possible association between breast implants and the development of anaplastic large cell lymphoma (ALCL) was first identified in 2011. At that time, there were not enough cases of to determine what factors increased a patient’s risk of developing the disease. As more information became available, the World Health Organization designated BIA-ALCL as a T-cell lymphoma that can develop following breast implants.
(BIA-ALCL), including nine deaths.
This figure includes all medical device reports received by the agency between 2011 and September 2017. The FDA recently provided an update on ALCL linked to breast implants and an estimate of lifetime risk of developing ALCL.
Based on available medical literature, the lifetime risk of developing BIA-ALCL for patients with textured breast implants ranges from 1 in 3,817 to 1 in 30,000, according to the update.
Of the 272 reports with data on surface type, 242 were textured implants and 30 were smooth implants. In addition, 413 reports include information on the implant fill type: 234 used silicone gel and 179 were saline filled.
“The FDA has been closely tracking the relationship between breast implants and a rare type of non-Hodgkin’s lymphoma since we first identified this possible association. We’ve been working to gather additional information to better characterize and quantify the risk so that patients and providers can have more informed discussions about breast implants,” said Binita Ashar, MD, director of the division of surgical devices in the FDA’s Center for Devices and Radiological Health. “As part of that effort, we are working to update and enhance the information we have on this association, including updating the total number of known cases of BIA-ALCL and the lifetime risk of developing BIA-ALCL as reported in medical literature.”
The possible association between breast implants and the development of anaplastic large cell lymphoma (ALCL) was first identified in 2011. At that time, there were not enough cases of to determine what factors increased a patient’s risk of developing the disease. As more information became available, the World Health Organization designated BIA-ALCL as a T-cell lymphoma that can develop following breast implants.
Serial entrepreneur examines the risk-to-reward ratio balance in GI innovation
BOSTON – Just out of fellowship, Christopher C. Thompson, MD, director of therapeutic endoscopy, Brigham and Women’s Hospital, Boston, adapted an antireflux suturing device for use in a bariatric procedure. It worked so well he began using it routinely and taught others the technique. That was the first step in a journey that has taken him from consulting with industry to a founder of start-ups.
“The device company heard about what we were doing and were interested,” Dr. Thompson recounted during his How-I-Did-It lecture at the 2018 AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology. In the end, he served as a consultant in the development of a new suturing device specific for the bariatric procedure. This included helping secure a patent and learning first-hand what steps are needed to get a device to market.
“I do not have any regrets. It was good for my career and fun to be involved, but there was not much financial gain for me or for my department,” Dr. Thompson said.
His subsequent experience with licensing was an incremental step forward. In one example, he worked on developing an endoscopic simulator, an important unmet need both for teaching and evaluating skills in diagnostic colonoscopy, including a kinematic analysis that helped identify techniques that are associated with high levels of skill.
“We developed the technology in-house through a series of grants. The risks were low, but the rewards were better because the money helped fund activities in our department,” he said.
That device, too, has been very successful, but Dr. Thompson said it is important to recognize how far innovation can go when the work stays in the academic setting and the goal is licensing the technology. More recently, he took a nonsurgical anastomosis device through preclinical testing, but he was then unable to attract a device company for the next steps of development.
“With no one interested, we created a start-up,” Dr. Thompson said. The company, GI Windows, has now taken this product, a magnetic endo-luminal anastomosis bypass device for the treatment of diabetes mellitus, into advanced stages of clinical testing. Relative to licensing arrangements, this involved a different level of participation.
“A start-up means creating a board, raising money, and being involved in details that can involve a lot of heavy lifting,” Dr. Thompson said. “It is basically a second job.”
The ongoing clinical studies in patients with diabetes have been very encouraging. Dr. Thompson reported that a large proportion of patients with diabetes fitted with the device have been able to reduce or discontinue their antidiabetic medications, and high rates of excess weight loss have been documented.
GI Windows was created for the sole purpose of developing the anastomosis device, but Dr. Thompson was also involved in creating another company, now sold, that started without a specific device in mind.
“The products we developed were just from brainstorming on unmet needs, and we had several successes. That was a chance to learn new areas of the business, including building a sales force and learning how to get involved in international distribution, which were separate from trying simply to produce a viable clinical tool,” he said.
Creating companies, rather than licensing ideas, trades higher risk for greater reward, but Dr. Thompson emphasized that these rewards are not just financial.
“It is exciting to develop a team you trust, get a successful company off the ground, and watch it grow,” Dr. Thompson said. He indicated that the risk-to-reward calculation should not be undertaken independent of the value of the learning experience.
BOSTON – Just out of fellowship, Christopher C. Thompson, MD, director of therapeutic endoscopy, Brigham and Women’s Hospital, Boston, adapted an antireflux suturing device for use in a bariatric procedure. It worked so well he began using it routinely and taught others the technique. That was the first step in a journey that has taken him from consulting with industry to a founder of start-ups.
“The device company heard about what we were doing and were interested,” Dr. Thompson recounted during his How-I-Did-It lecture at the 2018 AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology. In the end, he served as a consultant in the development of a new suturing device specific for the bariatric procedure. This included helping secure a patent and learning first-hand what steps are needed to get a device to market.
“I do not have any regrets. It was good for my career and fun to be involved, but there was not much financial gain for me or for my department,” Dr. Thompson said.
His subsequent experience with licensing was an incremental step forward. In one example, he worked on developing an endoscopic simulator, an important unmet need both for teaching and evaluating skills in diagnostic colonoscopy, including a kinematic analysis that helped identify techniques that are associated with high levels of skill.
“We developed the technology in-house through a series of grants. The risks were low, but the rewards were better because the money helped fund activities in our department,” he said.
That device, too, has been very successful, but Dr. Thompson said it is important to recognize how far innovation can go when the work stays in the academic setting and the goal is licensing the technology. More recently, he took a nonsurgical anastomosis device through preclinical testing, but he was then unable to attract a device company for the next steps of development.
“With no one interested, we created a start-up,” Dr. Thompson said. The company, GI Windows, has now taken this product, a magnetic endo-luminal anastomosis bypass device for the treatment of diabetes mellitus, into advanced stages of clinical testing. Relative to licensing arrangements, this involved a different level of participation.
“A start-up means creating a board, raising money, and being involved in details that can involve a lot of heavy lifting,” Dr. Thompson said. “It is basically a second job.”
The ongoing clinical studies in patients with diabetes have been very encouraging. Dr. Thompson reported that a large proportion of patients with diabetes fitted with the device have been able to reduce or discontinue their antidiabetic medications, and high rates of excess weight loss have been documented.
GI Windows was created for the sole purpose of developing the anastomosis device, but Dr. Thompson was also involved in creating another company, now sold, that started without a specific device in mind.
“The products we developed were just from brainstorming on unmet needs, and we had several successes. That was a chance to learn new areas of the business, including building a sales force and learning how to get involved in international distribution, which were separate from trying simply to produce a viable clinical tool,” he said.
Creating companies, rather than licensing ideas, trades higher risk for greater reward, but Dr. Thompson emphasized that these rewards are not just financial.
“It is exciting to develop a team you trust, get a successful company off the ground, and watch it grow,” Dr. Thompson said. He indicated that the risk-to-reward calculation should not be undertaken independent of the value of the learning experience.
BOSTON – Just out of fellowship, Christopher C. Thompson, MD, director of therapeutic endoscopy, Brigham and Women’s Hospital, Boston, adapted an antireflux suturing device for use in a bariatric procedure. It worked so well he began using it routinely and taught others the technique. That was the first step in a journey that has taken him from consulting with industry to a founder of start-ups.
“The device company heard about what we were doing and were interested,” Dr. Thompson recounted during his How-I-Did-It lecture at the 2018 AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology. In the end, he served as a consultant in the development of a new suturing device specific for the bariatric procedure. This included helping secure a patent and learning first-hand what steps are needed to get a device to market.
“I do not have any regrets. It was good for my career and fun to be involved, but there was not much financial gain for me or for my department,” Dr. Thompson said.
His subsequent experience with licensing was an incremental step forward. In one example, he worked on developing an endoscopic simulator, an important unmet need both for teaching and evaluating skills in diagnostic colonoscopy, including a kinematic analysis that helped identify techniques that are associated with high levels of skill.
“We developed the technology in-house through a series of grants. The risks were low, but the rewards were better because the money helped fund activities in our department,” he said.
That device, too, has been very successful, but Dr. Thompson said it is important to recognize how far innovation can go when the work stays in the academic setting and the goal is licensing the technology. More recently, he took a nonsurgical anastomosis device through preclinical testing, but he was then unable to attract a device company for the next steps of development.
“With no one interested, we created a start-up,” Dr. Thompson said. The company, GI Windows, has now taken this product, a magnetic endo-luminal anastomosis bypass device for the treatment of diabetes mellitus, into advanced stages of clinical testing. Relative to licensing arrangements, this involved a different level of participation.
“A start-up means creating a board, raising money, and being involved in details that can involve a lot of heavy lifting,” Dr. Thompson said. “It is basically a second job.”
The ongoing clinical studies in patients with diabetes have been very encouraging. Dr. Thompson reported that a large proportion of patients with diabetes fitted with the device have been able to reduce or discontinue their antidiabetic medications, and high rates of excess weight loss have been documented.
GI Windows was created for the sole purpose of developing the anastomosis device, but Dr. Thompson was also involved in creating another company, now sold, that started without a specific device in mind.
“The products we developed were just from brainstorming on unmet needs, and we had several successes. That was a chance to learn new areas of the business, including building a sales force and learning how to get involved in international distribution, which were separate from trying simply to produce a viable clinical tool,” he said.
Creating companies, rather than licensing ideas, trades higher risk for greater reward, but Dr. Thompson emphasized that these rewards are not just financial.
“It is exciting to develop a team you trust, get a successful company off the ground, and watch it grow,” Dr. Thompson said. He indicated that the risk-to-reward calculation should not be undertaken independent of the value of the learning experience.
REPORTING FROM 2018 AGA TECH SUMMIT
Study links RA flares after joint replacement to disease activity, not medications
Patients with the most severe cases of rheumatoid arthritis are more likely to suffer flares after knee or hip replacement surgery, a new study finds, and it doesn’t seem to matter whether they stop taking biologics before their operation.
“We found that the majority of patients had active disease at the time of surgery, contrary to prior statements that RA patients have inactive disease at the time they go for hip or knee replacement. In fact, the majority – 65% of the patients – reported a flare of RA within 6 weeks of surgery,” lead author Susan M. Goodman, MD, of Cornell University and the Hospital for Special Surgery, New York, said in an interview. “Surprisingly, although more of the flaring patients were taking potent biologics that had been withheld preoperatively, the major risk factor for flares was their baseline disease activity.”
According to Dr. Goodman, the researchers launched the study to better understand how medical decisions prior to joint replacement surgery affect the progress of RA afterward.
In terms of continuing RA drug treatment, she said, “the decision really hinges on the risk of infection versus the risk of flare, and we didn’t know the usual course of events for these patients.”
In addition, she said, “many doctors incorrectly think that the majority of patients with RA have ‘burnt-out’ or inactive disease at the time of hip or knee replacement surgery.”
For the study, the researchers prospectively followed 120 patients who were to undergo joint replacement surgery. (The researchers initially approached 354 patients, of whom 169 declined to participate. Another 65 were dropped from the study for various reasons, including 42 who did not sufficiently fill out questionnaires and were deleted from the final analysis.)
The researchers tracked the patients before surgery and for 6 weeks after surgery. A majority of the patients were female (83%) and white (81%), with a mean age of 62 and a median RA symptom duration of 15 years. A total of 44% underwent hip replacement surgery while the rest underwent knee replacement surgery. Just over half of the patients were taking biologics, which were stopped prior to surgery, while glucocorticoids and methotrexate were usually continued.
Just under two-thirds of the patients flared within the first 6 weeks after surgery. The researchers didn’t find any connection between the flares and stopping biologics or using methotrexate. They did, however, link higher baseline RA activity to postsurgery flaring (odds ratio, 2.11; P = .015).
Dr. Goodman said that she and her colleagues continue to collect data to better understand flares and the link to disease severity. “The long-term implications of this are not yet known. We would like to know the effect on long-term functional outcome and complication rate.”
The National Institutes of Health, the Weill Cornell Clinical Translational Science Center, and the Block Family Foundation supported the study. Dr. Goodman disclosed receiving research funding from Novartis and Roche.
SOURCE: Goodman S et al. J Rheumatol. 2018 Mar 15. doi: 10.3899/jrheum.170366
Patients with the most severe cases of rheumatoid arthritis are more likely to suffer flares after knee or hip replacement surgery, a new study finds, and it doesn’t seem to matter whether they stop taking biologics before their operation.
“We found that the majority of patients had active disease at the time of surgery, contrary to prior statements that RA patients have inactive disease at the time they go for hip or knee replacement. In fact, the majority – 65% of the patients – reported a flare of RA within 6 weeks of surgery,” lead author Susan M. Goodman, MD, of Cornell University and the Hospital for Special Surgery, New York, said in an interview. “Surprisingly, although more of the flaring patients were taking potent biologics that had been withheld preoperatively, the major risk factor for flares was their baseline disease activity.”
According to Dr. Goodman, the researchers launched the study to better understand how medical decisions prior to joint replacement surgery affect the progress of RA afterward.
In terms of continuing RA drug treatment, she said, “the decision really hinges on the risk of infection versus the risk of flare, and we didn’t know the usual course of events for these patients.”
In addition, she said, “many doctors incorrectly think that the majority of patients with RA have ‘burnt-out’ or inactive disease at the time of hip or knee replacement surgery.”
For the study, the researchers prospectively followed 120 patients who were to undergo joint replacement surgery. (The researchers initially approached 354 patients, of whom 169 declined to participate. Another 65 were dropped from the study for various reasons, including 42 who did not sufficiently fill out questionnaires and were deleted from the final analysis.)
The researchers tracked the patients before surgery and for 6 weeks after surgery. A majority of the patients were female (83%) and white (81%), with a mean age of 62 and a median RA symptom duration of 15 years. A total of 44% underwent hip replacement surgery while the rest underwent knee replacement surgery. Just over half of the patients were taking biologics, which were stopped prior to surgery, while glucocorticoids and methotrexate were usually continued.
Just under two-thirds of the patients flared within the first 6 weeks after surgery. The researchers didn’t find any connection between the flares and stopping biologics or using methotrexate. They did, however, link higher baseline RA activity to postsurgery flaring (odds ratio, 2.11; P = .015).
Dr. Goodman said that she and her colleagues continue to collect data to better understand flares and the link to disease severity. “The long-term implications of this are not yet known. We would like to know the effect on long-term functional outcome and complication rate.”
The National Institutes of Health, the Weill Cornell Clinical Translational Science Center, and the Block Family Foundation supported the study. Dr. Goodman disclosed receiving research funding from Novartis and Roche.
SOURCE: Goodman S et al. J Rheumatol. 2018 Mar 15. doi: 10.3899/jrheum.170366
Patients with the most severe cases of rheumatoid arthritis are more likely to suffer flares after knee or hip replacement surgery, a new study finds, and it doesn’t seem to matter whether they stop taking biologics before their operation.
“We found that the majority of patients had active disease at the time of surgery, contrary to prior statements that RA patients have inactive disease at the time they go for hip or knee replacement. In fact, the majority – 65% of the patients – reported a flare of RA within 6 weeks of surgery,” lead author Susan M. Goodman, MD, of Cornell University and the Hospital for Special Surgery, New York, said in an interview. “Surprisingly, although more of the flaring patients were taking potent biologics that had been withheld preoperatively, the major risk factor for flares was their baseline disease activity.”
According to Dr. Goodman, the researchers launched the study to better understand how medical decisions prior to joint replacement surgery affect the progress of RA afterward.
In terms of continuing RA drug treatment, she said, “the decision really hinges on the risk of infection versus the risk of flare, and we didn’t know the usual course of events for these patients.”
In addition, she said, “many doctors incorrectly think that the majority of patients with RA have ‘burnt-out’ or inactive disease at the time of hip or knee replacement surgery.”
For the study, the researchers prospectively followed 120 patients who were to undergo joint replacement surgery. (The researchers initially approached 354 patients, of whom 169 declined to participate. Another 65 were dropped from the study for various reasons, including 42 who did not sufficiently fill out questionnaires and were deleted from the final analysis.)
The researchers tracked the patients before surgery and for 6 weeks after surgery. A majority of the patients were female (83%) and white (81%), with a mean age of 62 and a median RA symptom duration of 15 years. A total of 44% underwent hip replacement surgery while the rest underwent knee replacement surgery. Just over half of the patients were taking biologics, which were stopped prior to surgery, while glucocorticoids and methotrexate were usually continued.
Just under two-thirds of the patients flared within the first 6 weeks after surgery. The researchers didn’t find any connection between the flares and stopping biologics or using methotrexate. They did, however, link higher baseline RA activity to postsurgery flaring (odds ratio, 2.11; P = .015).
Dr. Goodman said that she and her colleagues continue to collect data to better understand flares and the link to disease severity. “The long-term implications of this are not yet known. We would like to know the effect on long-term functional outcome and complication rate.”
The National Institutes of Health, the Weill Cornell Clinical Translational Science Center, and the Block Family Foundation supported the study. Dr. Goodman disclosed receiving research funding from Novartis and Roche.
SOURCE: Goodman S et al. J Rheumatol. 2018 Mar 15. doi: 10.3899/jrheum.170366
FROM JOURNAL OF RHEUMATOLOGY
Key clinical point:
Major finding: Sixty-five percent of RA patients developed flares after joint replacement surgery, and it was more common in those with higher baseline RA activity (odds ratio, 2.11; P = .015).
Study details: Prospective study of 120 patients with RA who underwent hip replacement (44%) or knee replacement (56%).
Disclosures: The National Institutes of Health, the Weill Cornell Clinical Translational Science Center, and the Block Family Foundation supported the study. The lead author disclosed receiving research funding from Novartis and Roche.
Source: Goodman S et al. J Rheumatol. 2018 Mar 15. doi: 10.3899/jrheum.170366.
Low microbiota diversity linked to poor survival after transplant
SALT LAKE CITY – A multicenter study confirmed that diversity of gut microbiota is associated with better survival after allogeneic hematopoietic cell transplantation (HCT), while low diversity and the predominance of pathogenic bacteria are linked to graft versus host disease (GVHD).
Lower calorie intake and exposure to broad-spectrum antibiotics were both associated with lower diversity, the study found.
“One of the striking findings early on was this association between diversity in the gut and overall survival,” said Jonathan Peled, MD, PhD, noting that his research group also saw that high gut diversity was associated with lower rates of GVHD-related mortality.
“The first question that I want to ask today is ‘Are the patterns of microbiota injury that have been described in single-center studies and their association with clinical outcomes consistent across geography?’” Dr. Peled said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
To answer this, Dr. Peled and his associates at Memorial Sloan Kettering Cancer Center (MSKCC), New York, teamed up with a research group at Duke University, Durham, N.C., and with investigators in Regensburg, Germany. The international group devised a study that would use centralized sequencing and analysis to examine patient fecal samples from all three centers.
In all, 5,310 samples were obtained from 1,034 HCT patients. MSKCC contributed most of the samples (n = 908, 87.8%), with Regensburg contributing 79 (7.6%) and Duke contributing 47 (4.5%).
The most common malignancies treated were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma. The balance of graft sources and conditioning intensity varied between centers, but overall, more than three-quarters of grafts were from peripheral blood stem cells and just over half of patients received myeloablative conditioning.
The centralized microbiota profiling involved extracting bacterial DNA, and then using polymerase chain reaction to amplify 16sRNA for sequencing and subsequent taxonomic identification.
“Samples can be segregated into clusters according to microbiota composition,” said Dr. Peled, a medical oncologist at MSKCC. The investigators used an algorithm called t-distributed stochastic neighbor embedding, or tSNE, to help detect patterns in microbiota composition and diversity before and throughout the HCT process. Visualizations using tSNE allow for two-dimensional representations of complicated associations and interrelatedness in data.
“Color-coded by diversity and time, we see that these early samples tend to be more diverse,” in the tSNE analyses, Dr. Peled said. The later clusters, he said, show evidence of lower diversity and injury.
Individual samples can also be coded in a way that shows clusters by abundance of various bacterial taxa, Dr. Peled said. “The early, diverse cluster tends to be dominated, or filled, by anaerobic commensals such as Firmicutes and Clostridia, which we and others have found are associated with good outcomes after transplant.”
The lower-diversity states seen later, after transplant, tend to be dominated by a variety of pathogenic bacteria, Dr. Peled said. These include Enterococcus and Proteobacteria, a phylum that includes Klebsiella and Escherichia coli species. This predominance has been associated with subsequent bacteremia, he said.
“Patients tend to enter transplant with a relatively diverse flora, and a frequent event in the posttransplant samples is domination by these pathobiomes,” Dr. Peled said. “In some cases, almost the entire composition of the gut is [composed] of a single species.” This loss of diversity and single-species domination was seen across the three geographically diverse research sites, he said.
This decimation of diversity is linked to poor transplant outcomes. In particular, Dr. Peled said, an enterococcus-dominated gut had previously been associated with higher risk for acute GVHD and with gastrointestinal GVHD.
Here, the multisite data showed that at Regensburg, higher enterococcus abundance on days 7-14 post HCT was associated with increased risk of GI GVHD. At MSKCC, enterococcus domination was associated with a hazard ratio of 1.4 for acute GVHD (P = .008). The MSKCC group used data from 503 patients, defining domination as at least 30% relative abundance in any sample from post-HCT days 7-21.
Patients at both MSKCC and Regensburg had a better chance of overall survival if they had high intestinal microbial diversity around the period of neutrophil engraftment, as seen in a sample collected within 7 days of post-HCT day 14. At MSKCC, data for 651 patients showed a statistically significant association (P = .006); this finding was reproduced at Regensburg, which also saw a significant association (P = .015) for the 59 patients studied, Dr. Peled reported.
Increased treatment-related mortality was seen for patients who had low microbial diversity following neutrophil engraftment as well. Of 372 MSKCC patients who had samples available 7-50 days after engraftment, high diversity was associated with better overall survival, and with lower treatment-related mortality (P = .03 for both).
Dr. Peled and his collaborators also divided patients into quartiles by amount of biodiversity. They found that comparing the highest to the lowest biodiversity quartile showed significantly overall survival benefits for the highest-diversity group (P = .007).
The problem starts before transplant, Dr. Peled explained. The researchers found that compared with healthy controls at MSKCC and data from the Human Microbiome Project, HCT patients entered their transplant with significantly less gut biodiversity.
The second question to be addressed is “What are the key environmental determinants of intestinal microbiota composition?” said Dr. Peled.
“Peri-HCT exposure to broad-spectrum antibiotics is associated with lower intestinal microbial diversity,” he said. For 5,936 samples taken from 976 patients receiving allogeneic HCT, the most significant difference in diversity between those with and without broad-spectrum antibiotic exposure was seen at day 15 post transplant (P = .008).
Higher calorie intake was also associated with greater diversity (P less than .001). Higher dietary fiber intake was associated with higher abundance of Blautia, a genus considered to be a healthy commensal microorganism, Dr. Peled said.
“Conditioning intensity is associated with the magnitude of diversity loss, and with distinct microbiome configurations,” said Dr. Peled. Using 4,311 samples from 908 patients, a myeloablative conditioning regimen (n = 508) was associated with significantly less diversity when compared with reduced intensity (n = 316) and nonmyeloablative regimens (n = 84; P =.002 and P less than .001, respectively).
To answer a third question – What is the natural history of recovery from microbiota injury after HCT? – the investigators looked at trends over time for 28 allogeneic HCT recipients. With a total of 294 samples for analysis, Dr. Peled and his group found that “diversity increases, but often to a configuration distinct from the pre-HCT state.” It took some patients nearly a year to return to their pretransplant level of diversity.
Patients in the subset of those who go on to develop lower gastrointestinal GVHD have an intestinal microbiota composition that is distinct from those patients whose GVHD exclusively involved the upper gastrointestinal tract, the skin, or the liver (P = .019), Dr. Peled said.
He and his team are currently enrolling patients for a phase 2 randomized clinical trial (NCT03078010) that will explore strategies to deescalate the use of broad-spectrum antibiotics for febrile neutropenia in patients with allogeneic HCT. The trial will randomize patients to receive either piperacillin-tazobactam, the current standard of care at MSKCC, or cefepime with deescalation to aztreonam with vancomycin, the microbiota-sparing strategy. The trial will examine the abundance of Clostridiales and Blautia species, gut biodiversity, the rate of GVHD, bacteremia, and survival rates.
The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics
SOURCE: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
SALT LAKE CITY – A multicenter study confirmed that diversity of gut microbiota is associated with better survival after allogeneic hematopoietic cell transplantation (HCT), while low diversity and the predominance of pathogenic bacteria are linked to graft versus host disease (GVHD).
Lower calorie intake and exposure to broad-spectrum antibiotics were both associated with lower diversity, the study found.
“One of the striking findings early on was this association between diversity in the gut and overall survival,” said Jonathan Peled, MD, PhD, noting that his research group also saw that high gut diversity was associated with lower rates of GVHD-related mortality.
“The first question that I want to ask today is ‘Are the patterns of microbiota injury that have been described in single-center studies and their association with clinical outcomes consistent across geography?’” Dr. Peled said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
To answer this, Dr. Peled and his associates at Memorial Sloan Kettering Cancer Center (MSKCC), New York, teamed up with a research group at Duke University, Durham, N.C., and with investigators in Regensburg, Germany. The international group devised a study that would use centralized sequencing and analysis to examine patient fecal samples from all three centers.
In all, 5,310 samples were obtained from 1,034 HCT patients. MSKCC contributed most of the samples (n = 908, 87.8%), with Regensburg contributing 79 (7.6%) and Duke contributing 47 (4.5%).
The most common malignancies treated were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma. The balance of graft sources and conditioning intensity varied between centers, but overall, more than three-quarters of grafts were from peripheral blood stem cells and just over half of patients received myeloablative conditioning.
The centralized microbiota profiling involved extracting bacterial DNA, and then using polymerase chain reaction to amplify 16sRNA for sequencing and subsequent taxonomic identification.
“Samples can be segregated into clusters according to microbiota composition,” said Dr. Peled, a medical oncologist at MSKCC. The investigators used an algorithm called t-distributed stochastic neighbor embedding, or tSNE, to help detect patterns in microbiota composition and diversity before and throughout the HCT process. Visualizations using tSNE allow for two-dimensional representations of complicated associations and interrelatedness in data.
“Color-coded by diversity and time, we see that these early samples tend to be more diverse,” in the tSNE analyses, Dr. Peled said. The later clusters, he said, show evidence of lower diversity and injury.
Individual samples can also be coded in a way that shows clusters by abundance of various bacterial taxa, Dr. Peled said. “The early, diverse cluster tends to be dominated, or filled, by anaerobic commensals such as Firmicutes and Clostridia, which we and others have found are associated with good outcomes after transplant.”
The lower-diversity states seen later, after transplant, tend to be dominated by a variety of pathogenic bacteria, Dr. Peled said. These include Enterococcus and Proteobacteria, a phylum that includes Klebsiella and Escherichia coli species. This predominance has been associated with subsequent bacteremia, he said.
“Patients tend to enter transplant with a relatively diverse flora, and a frequent event in the posttransplant samples is domination by these pathobiomes,” Dr. Peled said. “In some cases, almost the entire composition of the gut is [composed] of a single species.” This loss of diversity and single-species domination was seen across the three geographically diverse research sites, he said.
This decimation of diversity is linked to poor transplant outcomes. In particular, Dr. Peled said, an enterococcus-dominated gut had previously been associated with higher risk for acute GVHD and with gastrointestinal GVHD.
Here, the multisite data showed that at Regensburg, higher enterococcus abundance on days 7-14 post HCT was associated with increased risk of GI GVHD. At MSKCC, enterococcus domination was associated with a hazard ratio of 1.4 for acute GVHD (P = .008). The MSKCC group used data from 503 patients, defining domination as at least 30% relative abundance in any sample from post-HCT days 7-21.
Patients at both MSKCC and Regensburg had a better chance of overall survival if they had high intestinal microbial diversity around the period of neutrophil engraftment, as seen in a sample collected within 7 days of post-HCT day 14. At MSKCC, data for 651 patients showed a statistically significant association (P = .006); this finding was reproduced at Regensburg, which also saw a significant association (P = .015) for the 59 patients studied, Dr. Peled reported.
Increased treatment-related mortality was seen for patients who had low microbial diversity following neutrophil engraftment as well. Of 372 MSKCC patients who had samples available 7-50 days after engraftment, high diversity was associated with better overall survival, and with lower treatment-related mortality (P = .03 for both).
Dr. Peled and his collaborators also divided patients into quartiles by amount of biodiversity. They found that comparing the highest to the lowest biodiversity quartile showed significantly overall survival benefits for the highest-diversity group (P = .007).
The problem starts before transplant, Dr. Peled explained. The researchers found that compared with healthy controls at MSKCC and data from the Human Microbiome Project, HCT patients entered their transplant with significantly less gut biodiversity.
The second question to be addressed is “What are the key environmental determinants of intestinal microbiota composition?” said Dr. Peled.
“Peri-HCT exposure to broad-spectrum antibiotics is associated with lower intestinal microbial diversity,” he said. For 5,936 samples taken from 976 patients receiving allogeneic HCT, the most significant difference in diversity between those with and without broad-spectrum antibiotic exposure was seen at day 15 post transplant (P = .008).
Higher calorie intake was also associated with greater diversity (P less than .001). Higher dietary fiber intake was associated with higher abundance of Blautia, a genus considered to be a healthy commensal microorganism, Dr. Peled said.
“Conditioning intensity is associated with the magnitude of diversity loss, and with distinct microbiome configurations,” said Dr. Peled. Using 4,311 samples from 908 patients, a myeloablative conditioning regimen (n = 508) was associated with significantly less diversity when compared with reduced intensity (n = 316) and nonmyeloablative regimens (n = 84; P =.002 and P less than .001, respectively).
To answer a third question – What is the natural history of recovery from microbiota injury after HCT? – the investigators looked at trends over time for 28 allogeneic HCT recipients. With a total of 294 samples for analysis, Dr. Peled and his group found that “diversity increases, but often to a configuration distinct from the pre-HCT state.” It took some patients nearly a year to return to their pretransplant level of diversity.
Patients in the subset of those who go on to develop lower gastrointestinal GVHD have an intestinal microbiota composition that is distinct from those patients whose GVHD exclusively involved the upper gastrointestinal tract, the skin, or the liver (P = .019), Dr. Peled said.
He and his team are currently enrolling patients for a phase 2 randomized clinical trial (NCT03078010) that will explore strategies to deescalate the use of broad-spectrum antibiotics for febrile neutropenia in patients with allogeneic HCT. The trial will randomize patients to receive either piperacillin-tazobactam, the current standard of care at MSKCC, or cefepime with deescalation to aztreonam with vancomycin, the microbiota-sparing strategy. The trial will examine the abundance of Clostridiales and Blautia species, gut biodiversity, the rate of GVHD, bacteremia, and survival rates.
The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics
SOURCE: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
SALT LAKE CITY – A multicenter study confirmed that diversity of gut microbiota is associated with better survival after allogeneic hematopoietic cell transplantation (HCT), while low diversity and the predominance of pathogenic bacteria are linked to graft versus host disease (GVHD).
Lower calorie intake and exposure to broad-spectrum antibiotics were both associated with lower diversity, the study found.
“One of the striking findings early on was this association between diversity in the gut and overall survival,” said Jonathan Peled, MD, PhD, noting that his research group also saw that high gut diversity was associated with lower rates of GVHD-related mortality.
“The first question that I want to ask today is ‘Are the patterns of microbiota injury that have been described in single-center studies and their association with clinical outcomes consistent across geography?’” Dr. Peled said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
To answer this, Dr. Peled and his associates at Memorial Sloan Kettering Cancer Center (MSKCC), New York, teamed up with a research group at Duke University, Durham, N.C., and with investigators in Regensburg, Germany. The international group devised a study that would use centralized sequencing and analysis to examine patient fecal samples from all three centers.
In all, 5,310 samples were obtained from 1,034 HCT patients. MSKCC contributed most of the samples (n = 908, 87.8%), with Regensburg contributing 79 (7.6%) and Duke contributing 47 (4.5%).
The most common malignancies treated were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma. The balance of graft sources and conditioning intensity varied between centers, but overall, more than three-quarters of grafts were from peripheral blood stem cells and just over half of patients received myeloablative conditioning.
The centralized microbiota profiling involved extracting bacterial DNA, and then using polymerase chain reaction to amplify 16sRNA for sequencing and subsequent taxonomic identification.
“Samples can be segregated into clusters according to microbiota composition,” said Dr. Peled, a medical oncologist at MSKCC. The investigators used an algorithm called t-distributed stochastic neighbor embedding, or tSNE, to help detect patterns in microbiota composition and diversity before and throughout the HCT process. Visualizations using tSNE allow for two-dimensional representations of complicated associations and interrelatedness in data.
“Color-coded by diversity and time, we see that these early samples tend to be more diverse,” in the tSNE analyses, Dr. Peled said. The later clusters, he said, show evidence of lower diversity and injury.
Individual samples can also be coded in a way that shows clusters by abundance of various bacterial taxa, Dr. Peled said. “The early, diverse cluster tends to be dominated, or filled, by anaerobic commensals such as Firmicutes and Clostridia, which we and others have found are associated with good outcomes after transplant.”
The lower-diversity states seen later, after transplant, tend to be dominated by a variety of pathogenic bacteria, Dr. Peled said. These include Enterococcus and Proteobacteria, a phylum that includes Klebsiella and Escherichia coli species. This predominance has been associated with subsequent bacteremia, he said.
“Patients tend to enter transplant with a relatively diverse flora, and a frequent event in the posttransplant samples is domination by these pathobiomes,” Dr. Peled said. “In some cases, almost the entire composition of the gut is [composed] of a single species.” This loss of diversity and single-species domination was seen across the three geographically diverse research sites, he said.
This decimation of diversity is linked to poor transplant outcomes. In particular, Dr. Peled said, an enterococcus-dominated gut had previously been associated with higher risk for acute GVHD and with gastrointestinal GVHD.
Here, the multisite data showed that at Regensburg, higher enterococcus abundance on days 7-14 post HCT was associated with increased risk of GI GVHD. At MSKCC, enterococcus domination was associated with a hazard ratio of 1.4 for acute GVHD (P = .008). The MSKCC group used data from 503 patients, defining domination as at least 30% relative abundance in any sample from post-HCT days 7-21.
Patients at both MSKCC and Regensburg had a better chance of overall survival if they had high intestinal microbial diversity around the period of neutrophil engraftment, as seen in a sample collected within 7 days of post-HCT day 14. At MSKCC, data for 651 patients showed a statistically significant association (P = .006); this finding was reproduced at Regensburg, which also saw a significant association (P = .015) for the 59 patients studied, Dr. Peled reported.
Increased treatment-related mortality was seen for patients who had low microbial diversity following neutrophil engraftment as well. Of 372 MSKCC patients who had samples available 7-50 days after engraftment, high diversity was associated with better overall survival, and with lower treatment-related mortality (P = .03 for both).
Dr. Peled and his collaborators also divided patients into quartiles by amount of biodiversity. They found that comparing the highest to the lowest biodiversity quartile showed significantly overall survival benefits for the highest-diversity group (P = .007).
The problem starts before transplant, Dr. Peled explained. The researchers found that compared with healthy controls at MSKCC and data from the Human Microbiome Project, HCT patients entered their transplant with significantly less gut biodiversity.
The second question to be addressed is “What are the key environmental determinants of intestinal microbiota composition?” said Dr. Peled.
“Peri-HCT exposure to broad-spectrum antibiotics is associated with lower intestinal microbial diversity,” he said. For 5,936 samples taken from 976 patients receiving allogeneic HCT, the most significant difference in diversity between those with and without broad-spectrum antibiotic exposure was seen at day 15 post transplant (P = .008).
Higher calorie intake was also associated with greater diversity (P less than .001). Higher dietary fiber intake was associated with higher abundance of Blautia, a genus considered to be a healthy commensal microorganism, Dr. Peled said.
“Conditioning intensity is associated with the magnitude of diversity loss, and with distinct microbiome configurations,” said Dr. Peled. Using 4,311 samples from 908 patients, a myeloablative conditioning regimen (n = 508) was associated with significantly less diversity when compared with reduced intensity (n = 316) and nonmyeloablative regimens (n = 84; P =.002 and P less than .001, respectively).
To answer a third question – What is the natural history of recovery from microbiota injury after HCT? – the investigators looked at trends over time for 28 allogeneic HCT recipients. With a total of 294 samples for analysis, Dr. Peled and his group found that “diversity increases, but often to a configuration distinct from the pre-HCT state.” It took some patients nearly a year to return to their pretransplant level of diversity.
Patients in the subset of those who go on to develop lower gastrointestinal GVHD have an intestinal microbiota composition that is distinct from those patients whose GVHD exclusively involved the upper gastrointestinal tract, the skin, or the liver (P = .019), Dr. Peled said.
He and his team are currently enrolling patients for a phase 2 randomized clinical trial (NCT03078010) that will explore strategies to deescalate the use of broad-spectrum antibiotics for febrile neutropenia in patients with allogeneic HCT. The trial will randomize patients to receive either piperacillin-tazobactam, the current standard of care at MSKCC, or cefepime with deescalation to aztreonam with vancomycin, the microbiota-sparing strategy. The trial will examine the abundance of Clostridiales and Blautia species, gut biodiversity, the rate of GVHD, bacteremia, and survival rates.
The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics
SOURCE: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: High microbiota diversity post transplant was associated with better overall survival at two sites (P = .006 and P = .015).
Study details: Multicenter study of 5,310 fecal samples obtained from 1,034 hematopoietic cell transplant recipients.
Disclosures: The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics.
Source: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
Chemotherapy, metabolic pathway may affect CAR T-cell potential
Two critical factors – prior exposure to chemotherapy and a glycolytic metabolism – appear to degrade the potential of T cells to become chimeric antigen receptor–T cells.
Chemotherapy, especially with cyclophosphamide and doxorubicin, seems particularly toxic to T cells, damaging the mitochondria and decreasing the cells’ spare respiratory capacity – a measure of mitochondrial health, David Barrett, MD, said during a press briefing held in advance of the annual meeting of the American Association for Cancer Research.
These new findings may help explain why children with acute lymphoblastic leukemia (ALL) tend to respond so vigorously to CAR T treatment, and why T cells from patients with solid tumors simply don’t grow, or die soon after patient infusion, he said in an interview. They also suggest a benefit of harvesting T cells before any chemotherapy, a procedure Dr. Barrett and his colleagues have advocated.
“Based on these data we have altered our practice for T-cell therapy in high-risk leukemia patients. If we have a patient who may have a poor prognosis, we try to collect the cells early and store them before proceeding, because we know chemotherapy will progressively degrade them.”
There still is no successful CAR T-cell protocol for solid tumors, but Dr. Barrett said these findings eventually may help such patients, particularly if more advanced experiments in manipulating the cells’ metabolism prove successful.
He and his colleagues investigated why T cells from some patients result in a poor clinical product that either fails manufacture or does not proliferate in the patient. They examined T cells from 157 pediatric patients with a variety of cancers, including ALL, non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, Hodgkin disease, chronic myelogenous leukemia, and Ewing sarcoma. The team obtained cells at diagnosis and after each cycle of chemotherapy.
They examined how well the cells grew in the transformation and expansion process. A “pass” was considered a fivefold expansion in response to CD3/CD28 exposure for 7 days. Normal donor cells typically expand 20- to 30-fold in this time.
Only T cells taken from ALL and Wilms tumor patients before chemotherapy achieved a pass, Dr. Barrett said. Most of the ALL expansions (80%) and half of the Wilms tumor expansions passed. “We noted very poor CAR T-cell potential in all the other tumor types – less than a 30% pass. We noted a decline in potential with cumulative chemotherapy in all cases, though this was particularly significant in children less than 3 years old.”
The team also used RNA profiling to look at the cells’ metabolic pathways. Dr. Barrett noted that T cells are highly metabolically adaptable, capable of using several different fuel types and switching from one to another. Glucose and fatty acids are frequent fuels. Most of the cells from patients with solid tumors exhibited a glycolytic metabolism, while cells from patients with ALL and Wilms tumor appeared to rely more on fatty acids.
“One is not inherently worse than the other,” he said. “But glycolysis appears to be a bad thing when we’re trying to turn them into CAR T cells. Those T cells were too exhausted to do anything.”
However, Dr. Barrett encouraged the cells to switch fuels by treating them in vitro with palmitic acid, the most common fatty acid in plants and animals.
“We were growing the cells in a media containing sugar, fatty acids, and amino acids,” he explained. “We just started overloading them with palmitic acid, which has a natural transporter on the T-cell surface, so it already had a good pathway to get into the cell. It helped restore some of the performance of these T cells in some assays, although it wasn’t a complete reversal. But it was encouraging that something as simple as providing an alternate fuel was enough to get some positive effect. Whether or not we would also have to block glucose use to get it to really work is something we continue to study.”
T cells that had been exposed to chemotherapy also did poorly. Cyclophosphamide and doxorubicin seemed particularly toxic. Cells with exposure to these two agents had severely depleted CAR T cell potential with very poor spare respiratory capacity. This is a marker of mitochondrial injury, Dr. Barrett said. “That wasn’t a huge surprise. We already knew that cyclophosphamide is very toxic to T cells.”
But the finding did suggest the simple intervention of harvesting T cells before chemotherapy, which is what Dr. Barrett and his colleagues now do in their high-risk ALL patients. Whether or not this would improve response in patients with solid tumors is still unknown.
He had no financial disclosures. This study was supported by the AACR, the Doris Duke Charitable Foundation Clinical Science Development Award, the Jeffrey Pride Foundation Research Award, and the St. Baldrick’s Foundation Scholar Award.
SOURCE: Barrett DM et al. AACR 2018, Abstract 1631.
Two critical factors – prior exposure to chemotherapy and a glycolytic metabolism – appear to degrade the potential of T cells to become chimeric antigen receptor–T cells.
Chemotherapy, especially with cyclophosphamide and doxorubicin, seems particularly toxic to T cells, damaging the mitochondria and decreasing the cells’ spare respiratory capacity – a measure of mitochondrial health, David Barrett, MD, said during a press briefing held in advance of the annual meeting of the American Association for Cancer Research.
These new findings may help explain why children with acute lymphoblastic leukemia (ALL) tend to respond so vigorously to CAR T treatment, and why T cells from patients with solid tumors simply don’t grow, or die soon after patient infusion, he said in an interview. They also suggest a benefit of harvesting T cells before any chemotherapy, a procedure Dr. Barrett and his colleagues have advocated.
“Based on these data we have altered our practice for T-cell therapy in high-risk leukemia patients. If we have a patient who may have a poor prognosis, we try to collect the cells early and store them before proceeding, because we know chemotherapy will progressively degrade them.”
There still is no successful CAR T-cell protocol for solid tumors, but Dr. Barrett said these findings eventually may help such patients, particularly if more advanced experiments in manipulating the cells’ metabolism prove successful.
He and his colleagues investigated why T cells from some patients result in a poor clinical product that either fails manufacture or does not proliferate in the patient. They examined T cells from 157 pediatric patients with a variety of cancers, including ALL, non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, Hodgkin disease, chronic myelogenous leukemia, and Ewing sarcoma. The team obtained cells at diagnosis and after each cycle of chemotherapy.
They examined how well the cells grew in the transformation and expansion process. A “pass” was considered a fivefold expansion in response to CD3/CD28 exposure for 7 days. Normal donor cells typically expand 20- to 30-fold in this time.
Only T cells taken from ALL and Wilms tumor patients before chemotherapy achieved a pass, Dr. Barrett said. Most of the ALL expansions (80%) and half of the Wilms tumor expansions passed. “We noted very poor CAR T-cell potential in all the other tumor types – less than a 30% pass. We noted a decline in potential with cumulative chemotherapy in all cases, though this was particularly significant in children less than 3 years old.”
The team also used RNA profiling to look at the cells’ metabolic pathways. Dr. Barrett noted that T cells are highly metabolically adaptable, capable of using several different fuel types and switching from one to another. Glucose and fatty acids are frequent fuels. Most of the cells from patients with solid tumors exhibited a glycolytic metabolism, while cells from patients with ALL and Wilms tumor appeared to rely more on fatty acids.
“One is not inherently worse than the other,” he said. “But glycolysis appears to be a bad thing when we’re trying to turn them into CAR T cells. Those T cells were too exhausted to do anything.”
However, Dr. Barrett encouraged the cells to switch fuels by treating them in vitro with palmitic acid, the most common fatty acid in plants and animals.
“We were growing the cells in a media containing sugar, fatty acids, and amino acids,” he explained. “We just started overloading them with palmitic acid, which has a natural transporter on the T-cell surface, so it already had a good pathway to get into the cell. It helped restore some of the performance of these T cells in some assays, although it wasn’t a complete reversal. But it was encouraging that something as simple as providing an alternate fuel was enough to get some positive effect. Whether or not we would also have to block glucose use to get it to really work is something we continue to study.”
T cells that had been exposed to chemotherapy also did poorly. Cyclophosphamide and doxorubicin seemed particularly toxic. Cells with exposure to these two agents had severely depleted CAR T cell potential with very poor spare respiratory capacity. This is a marker of mitochondrial injury, Dr. Barrett said. “That wasn’t a huge surprise. We already knew that cyclophosphamide is very toxic to T cells.”
But the finding did suggest the simple intervention of harvesting T cells before chemotherapy, which is what Dr. Barrett and his colleagues now do in their high-risk ALL patients. Whether or not this would improve response in patients with solid tumors is still unknown.
He had no financial disclosures. This study was supported by the AACR, the Doris Duke Charitable Foundation Clinical Science Development Award, the Jeffrey Pride Foundation Research Award, and the St. Baldrick’s Foundation Scholar Award.
SOURCE: Barrett DM et al. AACR 2018, Abstract 1631.
Two critical factors – prior exposure to chemotherapy and a glycolytic metabolism – appear to degrade the potential of T cells to become chimeric antigen receptor–T cells.
Chemotherapy, especially with cyclophosphamide and doxorubicin, seems particularly toxic to T cells, damaging the mitochondria and decreasing the cells’ spare respiratory capacity – a measure of mitochondrial health, David Barrett, MD, said during a press briefing held in advance of the annual meeting of the American Association for Cancer Research.
These new findings may help explain why children with acute lymphoblastic leukemia (ALL) tend to respond so vigorously to CAR T treatment, and why T cells from patients with solid tumors simply don’t grow, or die soon after patient infusion, he said in an interview. They also suggest a benefit of harvesting T cells before any chemotherapy, a procedure Dr. Barrett and his colleagues have advocated.
“Based on these data we have altered our practice for T-cell therapy in high-risk leukemia patients. If we have a patient who may have a poor prognosis, we try to collect the cells early and store them before proceeding, because we know chemotherapy will progressively degrade them.”
There still is no successful CAR T-cell protocol for solid tumors, but Dr. Barrett said these findings eventually may help such patients, particularly if more advanced experiments in manipulating the cells’ metabolism prove successful.
He and his colleagues investigated why T cells from some patients result in a poor clinical product that either fails manufacture or does not proliferate in the patient. They examined T cells from 157 pediatric patients with a variety of cancers, including ALL, non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, Hodgkin disease, chronic myelogenous leukemia, and Ewing sarcoma. The team obtained cells at diagnosis and after each cycle of chemotherapy.
They examined how well the cells grew in the transformation and expansion process. A “pass” was considered a fivefold expansion in response to CD3/CD28 exposure for 7 days. Normal donor cells typically expand 20- to 30-fold in this time.
Only T cells taken from ALL and Wilms tumor patients before chemotherapy achieved a pass, Dr. Barrett said. Most of the ALL expansions (80%) and half of the Wilms tumor expansions passed. “We noted very poor CAR T-cell potential in all the other tumor types – less than a 30% pass. We noted a decline in potential with cumulative chemotherapy in all cases, though this was particularly significant in children less than 3 years old.”
The team also used RNA profiling to look at the cells’ metabolic pathways. Dr. Barrett noted that T cells are highly metabolically adaptable, capable of using several different fuel types and switching from one to another. Glucose and fatty acids are frequent fuels. Most of the cells from patients with solid tumors exhibited a glycolytic metabolism, while cells from patients with ALL and Wilms tumor appeared to rely more on fatty acids.
“One is not inherently worse than the other,” he said. “But glycolysis appears to be a bad thing when we’re trying to turn them into CAR T cells. Those T cells were too exhausted to do anything.”
However, Dr. Barrett encouraged the cells to switch fuels by treating them in vitro with palmitic acid, the most common fatty acid in plants and animals.
“We were growing the cells in a media containing sugar, fatty acids, and amino acids,” he explained. “We just started overloading them with palmitic acid, which has a natural transporter on the T-cell surface, so it already had a good pathway to get into the cell. It helped restore some of the performance of these T cells in some assays, although it wasn’t a complete reversal. But it was encouraging that something as simple as providing an alternate fuel was enough to get some positive effect. Whether or not we would also have to block glucose use to get it to really work is something we continue to study.”
T cells that had been exposed to chemotherapy also did poorly. Cyclophosphamide and doxorubicin seemed particularly toxic. Cells with exposure to these two agents had severely depleted CAR T cell potential with very poor spare respiratory capacity. This is a marker of mitochondrial injury, Dr. Barrett said. “That wasn’t a huge surprise. We already knew that cyclophosphamide is very toxic to T cells.”
But the finding did suggest the simple intervention of harvesting T cells before chemotherapy, which is what Dr. Barrett and his colleagues now do in their high-risk ALL patients. Whether or not this would improve response in patients with solid tumors is still unknown.
He had no financial disclosures. This study was supported by the AACR, the Doris Duke Charitable Foundation Clinical Science Development Award, the Jeffrey Pride Foundation Research Award, and the St. Baldrick’s Foundation Scholar Award.
SOURCE: Barrett DM et al. AACR 2018, Abstract 1631.
FROM AACR 2018
Key clinical point: Prior exposure to chemotherapy may degrade the potential of T cells to become CAR T cells, suggesting a benefit of harvesting T cells before any chemotherapy.
Major finding: Only T cells taken from ALL and Wilm’s tumor patients before chemotherapy achieved a fivefold expansion in response to CD3/CD28 exposure for 7 days.
Study details: An examination of T cells from 157 pediatric patients with a variety of cancers at diagnosis and after each cycle of chemotherapy.
Disclosures: The study was supported by the American Association of Cancer Research, the Doris Duke Charitable Foundation Clinical Science Development Award, the Jeffrey Pride Foundation Research Award, and the St. Baldrick’s Foundation Scholar Award. Dr. Barrett and his coauthors had no financial disclosures.
Source: Barrett DM et al. AACR 2018, Abstract 1631.
Maternal biologic therapy does not affect infant vaccine responses
MAUI, HAWAII – The infants of inflammatory bowel disease patients on biologic therapy during pregnancy and breastfeeding do not have a diminished response rate to the inactivated vaccines routinely given during the first 6 months of life, Uma Mahadevan, MD, said at the 2018 Rheumatology Winter Clinical Symposium.
“Those babies are going to have detectable levels of drug on board, but they respond to vaccines just as well as infants born to mothers with IBD who were not on biologic therapy. The rates are the same, albeit lower than in the general population,” according to Dr. Mahadevan, professor of medicine and medical director of the Center for Colitis and Crohn’s Disease at the University of California, San Francisco.
Previous reports from the national registry have established that continuation of biologics in IBD patients throughout pregnancy and breastfeeding to maintain disease control poses no increased risks to the fetus in terms of rates of congenital anomalies, spontaneous abortion, intrauterine growth restriction, low birth weight, or longer-term developmental delay, compared with unexposed babies whose mothers have IBD.
Dr. Ananthakrishnan’s analysis focused on response rates to tetanus and Haemophilus influenzae B vaccines in the infants of 179 PIANO patients. Sixty-five percent of the IBD patients were on various biologic agents during pregnancy, 8% were on a thiopurine, 21% were on combination therapy, and 6% weren’t exposed to any IBD medications. Serologic studies showed that there was no difference across the four groups in terms of infant rates of protective titers in response to the vaccines. However, the 69%-84% rates of protective titers in the four groups fell short of the 90%-plus rate expected in the general population.
Live virus vaccines are contraindicated in the first 6 months of life in infants exposed to maternal biologics in utero. The only live virus vaccine given during that time frame in the United States is rotavirus, administered at months 2 and 3. Dr. Mahadevan and others recommend skipping that vaccine in babies exposed in utero to any IBD biologic other than certolizumab pegol (Cimzia), which uniquely doesn’t cross the placenta.
“That being said, infants born to 71 of our PIANO participants on anti-TNF therapy in pregnancy inadvertently got the rotavirus vaccine, and they were all just fine, even with very high drug levels,” the gastroenterologist said.
The live virus varicella and MMR vaccines can safely be given as scheduled at 1 year of age. By that time the biologics are long gone from the child.
Dr. Mahadevan reported receiving research funding from the Crohn’s and Colitis Foundation of America, which sponsors the PIANO registry. She also has financial relationships with several pharmaceutical companies.
MAUI, HAWAII – The infants of inflammatory bowel disease patients on biologic therapy during pregnancy and breastfeeding do not have a diminished response rate to the inactivated vaccines routinely given during the first 6 months of life, Uma Mahadevan, MD, said at the 2018 Rheumatology Winter Clinical Symposium.
“Those babies are going to have detectable levels of drug on board, but they respond to vaccines just as well as infants born to mothers with IBD who were not on biologic therapy. The rates are the same, albeit lower than in the general population,” according to Dr. Mahadevan, professor of medicine and medical director of the Center for Colitis and Crohn’s Disease at the University of California, San Francisco.
Previous reports from the national registry have established that continuation of biologics in IBD patients throughout pregnancy and breastfeeding to maintain disease control poses no increased risks to the fetus in terms of rates of congenital anomalies, spontaneous abortion, intrauterine growth restriction, low birth weight, or longer-term developmental delay, compared with unexposed babies whose mothers have IBD.
Dr. Ananthakrishnan’s analysis focused on response rates to tetanus and Haemophilus influenzae B vaccines in the infants of 179 PIANO patients. Sixty-five percent of the IBD patients were on various biologic agents during pregnancy, 8% were on a thiopurine, 21% were on combination therapy, and 6% weren’t exposed to any IBD medications. Serologic studies showed that there was no difference across the four groups in terms of infant rates of protective titers in response to the vaccines. However, the 69%-84% rates of protective titers in the four groups fell short of the 90%-plus rate expected in the general population.
Live virus vaccines are contraindicated in the first 6 months of life in infants exposed to maternal biologics in utero. The only live virus vaccine given during that time frame in the United States is rotavirus, administered at months 2 and 3. Dr. Mahadevan and others recommend skipping that vaccine in babies exposed in utero to any IBD biologic other than certolizumab pegol (Cimzia), which uniquely doesn’t cross the placenta.
“That being said, infants born to 71 of our PIANO participants on anti-TNF therapy in pregnancy inadvertently got the rotavirus vaccine, and they were all just fine, even with very high drug levels,” the gastroenterologist said.
The live virus varicella and MMR vaccines can safely be given as scheduled at 1 year of age. By that time the biologics are long gone from the child.
Dr. Mahadevan reported receiving research funding from the Crohn’s and Colitis Foundation of America, which sponsors the PIANO registry. She also has financial relationships with several pharmaceutical companies.
MAUI, HAWAII – The infants of inflammatory bowel disease patients on biologic therapy during pregnancy and breastfeeding do not have a diminished response rate to the inactivated vaccines routinely given during the first 6 months of life, Uma Mahadevan, MD, said at the 2018 Rheumatology Winter Clinical Symposium.
“Those babies are going to have detectable levels of drug on board, but they respond to vaccines just as well as infants born to mothers with IBD who were not on biologic therapy. The rates are the same, albeit lower than in the general population,” according to Dr. Mahadevan, professor of medicine and medical director of the Center for Colitis and Crohn’s Disease at the University of California, San Francisco.
Previous reports from the national registry have established that continuation of biologics in IBD patients throughout pregnancy and breastfeeding to maintain disease control poses no increased risks to the fetus in terms of rates of congenital anomalies, spontaneous abortion, intrauterine growth restriction, low birth weight, or longer-term developmental delay, compared with unexposed babies whose mothers have IBD.
Dr. Ananthakrishnan’s analysis focused on response rates to tetanus and Haemophilus influenzae B vaccines in the infants of 179 PIANO patients. Sixty-five percent of the IBD patients were on various biologic agents during pregnancy, 8% were on a thiopurine, 21% were on combination therapy, and 6% weren’t exposed to any IBD medications. Serologic studies showed that there was no difference across the four groups in terms of infant rates of protective titers in response to the vaccines. However, the 69%-84% rates of protective titers in the four groups fell short of the 90%-plus rate expected in the general population.
Live virus vaccines are contraindicated in the first 6 months of life in infants exposed to maternal biologics in utero. The only live virus vaccine given during that time frame in the United States is rotavirus, administered at months 2 and 3. Dr. Mahadevan and others recommend skipping that vaccine in babies exposed in utero to any IBD biologic other than certolizumab pegol (Cimzia), which uniquely doesn’t cross the placenta.
“That being said, infants born to 71 of our PIANO participants on anti-TNF therapy in pregnancy inadvertently got the rotavirus vaccine, and they were all just fine, even with very high drug levels,” the gastroenterologist said.
The live virus varicella and MMR vaccines can safely be given as scheduled at 1 year of age. By that time the biologics are long gone from the child.
Dr. Mahadevan reported receiving research funding from the Crohn’s and Colitis Foundation of America, which sponsors the PIANO registry. She also has financial relationships with several pharmaceutical companies.
EXPERT ANALYSIS FROM RWCS 2018