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Botulinum toxin injections: Err on the side of undercorrecting in first-time users
NEW YORK – In patients receiving first-time botulinum toxin injections for cosmetic enhancements, it is prudent to use a relatively low dose, Gary Goldenberg, MD, advised at the American Academy of Dermatology summer meeting.
Optimal dosing varies by individual, and undertreatment is easier to correct than is excess treatment. “This is a pearl. I always undercorrect, especially if I am injecting a patient for the first time,” said Dr. Goldenberg, an assistant clinical professor of dermatology and pathology at the Icahn School of Medicine at Mount Sinai, New York.
All patients are invited to return 2 weeks after their initial treatments, when the maximum effect is reached. Dr. Goldenberg does not charge for touch-ups administered at that time. “I want the patient to have the best possible experience,” he said.
The demand for botulinum toxin injections is skyrocketing, even among patients in their 20s. Also, men now represent a substantial proportion of those seeking cosmetic botulinum toxin injections.
Botulinum toxin injections are a source of high levels of patient satisfaction, according to Dr. Goldenberg. They are also a good way to get started in performing cosmetic procedures as skills in the injection of botulinum toxin are readily acquired, While some primary care physicians and gynecologists also are offering botulinum toxin injections for cosmetic purposes, dermatologists “are going to do a better job because we know the anatomy the best,” he said.
Dr. Goldenberg said botulinum toxin injections should be offered as a service in promotional efforts for one’s practice, but any mention to patients should be tactful. Patients should be informed that there are solutions for damaged or wrinkled skin, but the topic should be dropped if there is no apparent interest.
“I only suggest. I do not push,” he said. “I never talk about money. If they want to know how much (injections) will cost, they must speak to my office staff.”
With the recent approval of prabotulinumtoxinA (Jeuveau), there are four botulinum toxin injection products available in the United States. These include the original product, onabotulinumtoxinA (Botox), incobotulinumtoxinA (Xeomin), and abobotulinumtoxinA (Dysport). Dr. Goldenberg, who has administered them all, is not so far convinced there are important differences between them in regard to either efficacy or safety.
“There is another product now in clinical trials, so perhaps we will have a fifth product in a year or so,” said Dr. Goldenberg, who noted that the competition has resulted in claims and counterclaims regarding such issues as speed of onset and durability.
For dermatologists new to providing botulinum toxin injections, Dr. Goldenberg suggested restricting initial procedures to the face, particularly glabellar lines for which all of the available products are indicated. The companies that make these products also should offer a broad array of resources for improving skills, he said.
Dr. Goldenberg reports no potential conflicts of interest with companies that make botulinum toxins.
NEW YORK – In patients receiving first-time botulinum toxin injections for cosmetic enhancements, it is prudent to use a relatively low dose, Gary Goldenberg, MD, advised at the American Academy of Dermatology summer meeting.
Optimal dosing varies by individual, and undertreatment is easier to correct than is excess treatment. “This is a pearl. I always undercorrect, especially if I am injecting a patient for the first time,” said Dr. Goldenberg, an assistant clinical professor of dermatology and pathology at the Icahn School of Medicine at Mount Sinai, New York.
All patients are invited to return 2 weeks after their initial treatments, when the maximum effect is reached. Dr. Goldenberg does not charge for touch-ups administered at that time. “I want the patient to have the best possible experience,” he said.
The demand for botulinum toxin injections is skyrocketing, even among patients in their 20s. Also, men now represent a substantial proportion of those seeking cosmetic botulinum toxin injections.
Botulinum toxin injections are a source of high levels of patient satisfaction, according to Dr. Goldenberg. They are also a good way to get started in performing cosmetic procedures as skills in the injection of botulinum toxin are readily acquired, While some primary care physicians and gynecologists also are offering botulinum toxin injections for cosmetic purposes, dermatologists “are going to do a better job because we know the anatomy the best,” he said.
Dr. Goldenberg said botulinum toxin injections should be offered as a service in promotional efforts for one’s practice, but any mention to patients should be tactful. Patients should be informed that there are solutions for damaged or wrinkled skin, but the topic should be dropped if there is no apparent interest.
“I only suggest. I do not push,” he said. “I never talk about money. If they want to know how much (injections) will cost, they must speak to my office staff.”
With the recent approval of prabotulinumtoxinA (Jeuveau), there are four botulinum toxin injection products available in the United States. These include the original product, onabotulinumtoxinA (Botox), incobotulinumtoxinA (Xeomin), and abobotulinumtoxinA (Dysport). Dr. Goldenberg, who has administered them all, is not so far convinced there are important differences between them in regard to either efficacy or safety.
“There is another product now in clinical trials, so perhaps we will have a fifth product in a year or so,” said Dr. Goldenberg, who noted that the competition has resulted in claims and counterclaims regarding such issues as speed of onset and durability.
For dermatologists new to providing botulinum toxin injections, Dr. Goldenberg suggested restricting initial procedures to the face, particularly glabellar lines for which all of the available products are indicated. The companies that make these products also should offer a broad array of resources for improving skills, he said.
Dr. Goldenberg reports no potential conflicts of interest with companies that make botulinum toxins.
NEW YORK – In patients receiving first-time botulinum toxin injections for cosmetic enhancements, it is prudent to use a relatively low dose, Gary Goldenberg, MD, advised at the American Academy of Dermatology summer meeting.
Optimal dosing varies by individual, and undertreatment is easier to correct than is excess treatment. “This is a pearl. I always undercorrect, especially if I am injecting a patient for the first time,” said Dr. Goldenberg, an assistant clinical professor of dermatology and pathology at the Icahn School of Medicine at Mount Sinai, New York.
All patients are invited to return 2 weeks after their initial treatments, when the maximum effect is reached. Dr. Goldenberg does not charge for touch-ups administered at that time. “I want the patient to have the best possible experience,” he said.
The demand for botulinum toxin injections is skyrocketing, even among patients in their 20s. Also, men now represent a substantial proportion of those seeking cosmetic botulinum toxin injections.
Botulinum toxin injections are a source of high levels of patient satisfaction, according to Dr. Goldenberg. They are also a good way to get started in performing cosmetic procedures as skills in the injection of botulinum toxin are readily acquired, While some primary care physicians and gynecologists also are offering botulinum toxin injections for cosmetic purposes, dermatologists “are going to do a better job because we know the anatomy the best,” he said.
Dr. Goldenberg said botulinum toxin injections should be offered as a service in promotional efforts for one’s practice, but any mention to patients should be tactful. Patients should be informed that there are solutions for damaged or wrinkled skin, but the topic should be dropped if there is no apparent interest.
“I only suggest. I do not push,” he said. “I never talk about money. If they want to know how much (injections) will cost, they must speak to my office staff.”
With the recent approval of prabotulinumtoxinA (Jeuveau), there are four botulinum toxin injection products available in the United States. These include the original product, onabotulinumtoxinA (Botox), incobotulinumtoxinA (Xeomin), and abobotulinumtoxinA (Dysport). Dr. Goldenberg, who has administered them all, is not so far convinced there are important differences between them in regard to either efficacy or safety.
“There is another product now in clinical trials, so perhaps we will have a fifth product in a year or so,” said Dr. Goldenberg, who noted that the competition has resulted in claims and counterclaims regarding such issues as speed of onset and durability.
For dermatologists new to providing botulinum toxin injections, Dr. Goldenberg suggested restricting initial procedures to the face, particularly glabellar lines for which all of the available products are indicated. The companies that make these products also should offer a broad array of resources for improving skills, he said.
Dr. Goldenberg reports no potential conflicts of interest with companies that make botulinum toxins.
EXPERT ANALYSIS FROM SUMMER AAD 2019
Beyond sunscreen: Skin cancer preventive agents finding a role
NEW YORK – (KCs) that deserves to be considered for selective use in at-risk patients, according to an update at the American Academy of Dermatology summer meeting.
In providing her perspective on the available options, Rebecca Hartman, MD, MPH, director of melanoma epidemiology at Brigham and Women’s Hospital, Boston, emphasized that the therapies are not interchangeable but deserve to be used selectively according to their relative protection and relative risks.
Of oral agents, she characterized two, nicotinamide and acitretin, as “clinic-ready.” Acitretin is “an oldie but goodie,” but there is an important issue of tolerability. In the published studies, 15%-39% of patients withdrew because of adverse events, according to Dr. Hartman, which suggests the need for a motivated patient.
In addition, acitretin can be esterified into etretinate, a teratogen that can persist as long as 3 years after the drug is discontinued, making this drug contraindicated in women of childbearing potential, she noted.
However, most patients in need of prophylaxis for KCs are older, so teratogenicity is not an issue. In her practice, she offers acitretin to patients who are developing three or more KCs per year, as well as in situations of extensive skin damage in which a course of acitretin might provide some degree of clearing.
“When you are faced with the potential of a large number of biopsies, you could start acitretin to see if lesions can be reduced,” Dr. Hartman said .
Prevention of KCs became somewhat more attractive as a routine practice following publication of a phase 3 trial with nicotinamide. In this study, nicotinamide, an over-the-counter water-soluble form of vitamin B3, was associated with significantly reduced nonmelanoma skin cancers, including KCs and actinic keratoses, relative to placebo (N Engl J Med. 2015 Oct 22;373[17]:1618-26). Importantly, there was no greater risk of adverse events relative to placebo.
When assessed individually, the relative reduction in squamous cell carcinomas (SCCs; P = .05) and basal cell carcinomas (P = .12) fell short of statistical significance, but there was a highly significant 13% reduction in actinic keratoses after 12 months (P less than .001). An increase in SCCs was observed after therapy was stopped, which led Dr. Hartman to conclude that nicotinamide must be used on a “use-it-or-lose-it” basis. However, she does routinely offer this option.
“When do I recommend nicotinamide? Any patient with multiple actinic keratoses who wants to get ahead of the game and wants something that is relative safe,” Dr. Hartman explained. She uses the same dosing employed in the study, which was 500 mg twice daily.
There are other options for chemoprevention of KCs, but they are less attractive.
For example, capecitabine is effective, but tolerability is an even greater issue with this agent than it is for acitretin. According to Dr. Hartman, “we use this therapy very rarely and only in select cases.” As an alternative to the 14 days on and 7 days off schedule used for treatment of cancer, capecitabine is sometimes better tolerated in a 7 day on and 7 day off schedule, she said.
Topical 5-fluorouracil with or without calcipotriol is another chemoprevention option for those who can tolerate a skin reaction that lasts several days, Dr. Hartman said. She cited one study that associated this therapy with a nearly 80% reduction in face and scalp SCC.
Ultimately, she offers 5-fluorouracil with or without calcipotriol to “patients who want an evidence-based chemoprevention,” but she indicated that patients must be motivated to endure the adverse effects.
Many remain unaware of the array of options for chemoprevention of KCs, but Dr. Hartman emphasized that this is an area of active research with new options expected.
“I am really excited about the future direction of chemoprevention in skin cancer,” said Dr. Hartman, citing ongoing work to develop vitamin A, polypodium leucotomas extract, and human papillomavirus vaccine as options.
“If we can stop skin cancer in the first place, avoiding the morbidity and mortality of treatment, we will also hopefully save costs as well,” she commented. So far, essentially all of the strategies for chemoprevention, other than sunscreen, involve KCs, which leaves a large unmet need for better ways to prevent melanoma. However, Dr. Hartman noted that KCs represent the most common type of cancer of any type.
Just days after Dr. Hartman spoke at the meeting, a prospective study of vitamin A that found an inverse association between vitamin A intake and cutaneous SCC risk was, in fact, published in JAMA Dermatology (2019 Jul 31. doi: 10.1001/jamadermatol.2019.1937).
Dr. Hartman reported no financial relationships relevant to her presentation.
NEW YORK – (KCs) that deserves to be considered for selective use in at-risk patients, according to an update at the American Academy of Dermatology summer meeting.
In providing her perspective on the available options, Rebecca Hartman, MD, MPH, director of melanoma epidemiology at Brigham and Women’s Hospital, Boston, emphasized that the therapies are not interchangeable but deserve to be used selectively according to their relative protection and relative risks.
Of oral agents, she characterized two, nicotinamide and acitretin, as “clinic-ready.” Acitretin is “an oldie but goodie,” but there is an important issue of tolerability. In the published studies, 15%-39% of patients withdrew because of adverse events, according to Dr. Hartman, which suggests the need for a motivated patient.
In addition, acitretin can be esterified into etretinate, a teratogen that can persist as long as 3 years after the drug is discontinued, making this drug contraindicated in women of childbearing potential, she noted.
However, most patients in need of prophylaxis for KCs are older, so teratogenicity is not an issue. In her practice, she offers acitretin to patients who are developing three or more KCs per year, as well as in situations of extensive skin damage in which a course of acitretin might provide some degree of clearing.
“When you are faced with the potential of a large number of biopsies, you could start acitretin to see if lesions can be reduced,” Dr. Hartman said .
Prevention of KCs became somewhat more attractive as a routine practice following publication of a phase 3 trial with nicotinamide. In this study, nicotinamide, an over-the-counter water-soluble form of vitamin B3, was associated with significantly reduced nonmelanoma skin cancers, including KCs and actinic keratoses, relative to placebo (N Engl J Med. 2015 Oct 22;373[17]:1618-26). Importantly, there was no greater risk of adverse events relative to placebo.
When assessed individually, the relative reduction in squamous cell carcinomas (SCCs; P = .05) and basal cell carcinomas (P = .12) fell short of statistical significance, but there was a highly significant 13% reduction in actinic keratoses after 12 months (P less than .001). An increase in SCCs was observed after therapy was stopped, which led Dr. Hartman to conclude that nicotinamide must be used on a “use-it-or-lose-it” basis. However, she does routinely offer this option.
“When do I recommend nicotinamide? Any patient with multiple actinic keratoses who wants to get ahead of the game and wants something that is relative safe,” Dr. Hartman explained. She uses the same dosing employed in the study, which was 500 mg twice daily.
There are other options for chemoprevention of KCs, but they are less attractive.
For example, capecitabine is effective, but tolerability is an even greater issue with this agent than it is for acitretin. According to Dr. Hartman, “we use this therapy very rarely and only in select cases.” As an alternative to the 14 days on and 7 days off schedule used for treatment of cancer, capecitabine is sometimes better tolerated in a 7 day on and 7 day off schedule, she said.
Topical 5-fluorouracil with or without calcipotriol is another chemoprevention option for those who can tolerate a skin reaction that lasts several days, Dr. Hartman said. She cited one study that associated this therapy with a nearly 80% reduction in face and scalp SCC.
Ultimately, she offers 5-fluorouracil with or without calcipotriol to “patients who want an evidence-based chemoprevention,” but she indicated that patients must be motivated to endure the adverse effects.
Many remain unaware of the array of options for chemoprevention of KCs, but Dr. Hartman emphasized that this is an area of active research with new options expected.
“I am really excited about the future direction of chemoprevention in skin cancer,” said Dr. Hartman, citing ongoing work to develop vitamin A, polypodium leucotomas extract, and human papillomavirus vaccine as options.
“If we can stop skin cancer in the first place, avoiding the morbidity and mortality of treatment, we will also hopefully save costs as well,” she commented. So far, essentially all of the strategies for chemoprevention, other than sunscreen, involve KCs, which leaves a large unmet need for better ways to prevent melanoma. However, Dr. Hartman noted that KCs represent the most common type of cancer of any type.
Just days after Dr. Hartman spoke at the meeting, a prospective study of vitamin A that found an inverse association between vitamin A intake and cutaneous SCC risk was, in fact, published in JAMA Dermatology (2019 Jul 31. doi: 10.1001/jamadermatol.2019.1937).
Dr. Hartman reported no financial relationships relevant to her presentation.
NEW YORK – (KCs) that deserves to be considered for selective use in at-risk patients, according to an update at the American Academy of Dermatology summer meeting.
In providing her perspective on the available options, Rebecca Hartman, MD, MPH, director of melanoma epidemiology at Brigham and Women’s Hospital, Boston, emphasized that the therapies are not interchangeable but deserve to be used selectively according to their relative protection and relative risks.
Of oral agents, she characterized two, nicotinamide and acitretin, as “clinic-ready.” Acitretin is “an oldie but goodie,” but there is an important issue of tolerability. In the published studies, 15%-39% of patients withdrew because of adverse events, according to Dr. Hartman, which suggests the need for a motivated patient.
In addition, acitretin can be esterified into etretinate, a teratogen that can persist as long as 3 years after the drug is discontinued, making this drug contraindicated in women of childbearing potential, she noted.
However, most patients in need of prophylaxis for KCs are older, so teratogenicity is not an issue. In her practice, she offers acitretin to patients who are developing three or more KCs per year, as well as in situations of extensive skin damage in which a course of acitretin might provide some degree of clearing.
“When you are faced with the potential of a large number of biopsies, you could start acitretin to see if lesions can be reduced,” Dr. Hartman said .
Prevention of KCs became somewhat more attractive as a routine practice following publication of a phase 3 trial with nicotinamide. In this study, nicotinamide, an over-the-counter water-soluble form of vitamin B3, was associated with significantly reduced nonmelanoma skin cancers, including KCs and actinic keratoses, relative to placebo (N Engl J Med. 2015 Oct 22;373[17]:1618-26). Importantly, there was no greater risk of adverse events relative to placebo.
When assessed individually, the relative reduction in squamous cell carcinomas (SCCs; P = .05) and basal cell carcinomas (P = .12) fell short of statistical significance, but there was a highly significant 13% reduction in actinic keratoses after 12 months (P less than .001). An increase in SCCs was observed after therapy was stopped, which led Dr. Hartman to conclude that nicotinamide must be used on a “use-it-or-lose-it” basis. However, she does routinely offer this option.
“When do I recommend nicotinamide? Any patient with multiple actinic keratoses who wants to get ahead of the game and wants something that is relative safe,” Dr. Hartman explained. She uses the same dosing employed in the study, which was 500 mg twice daily.
There are other options for chemoprevention of KCs, but they are less attractive.
For example, capecitabine is effective, but tolerability is an even greater issue with this agent than it is for acitretin. According to Dr. Hartman, “we use this therapy very rarely and only in select cases.” As an alternative to the 14 days on and 7 days off schedule used for treatment of cancer, capecitabine is sometimes better tolerated in a 7 day on and 7 day off schedule, she said.
Topical 5-fluorouracil with or without calcipotriol is another chemoprevention option for those who can tolerate a skin reaction that lasts several days, Dr. Hartman said. She cited one study that associated this therapy with a nearly 80% reduction in face and scalp SCC.
Ultimately, she offers 5-fluorouracil with or without calcipotriol to “patients who want an evidence-based chemoprevention,” but she indicated that patients must be motivated to endure the adverse effects.
Many remain unaware of the array of options for chemoprevention of KCs, but Dr. Hartman emphasized that this is an area of active research with new options expected.
“I am really excited about the future direction of chemoprevention in skin cancer,” said Dr. Hartman, citing ongoing work to develop vitamin A, polypodium leucotomas extract, and human papillomavirus vaccine as options.
“If we can stop skin cancer in the first place, avoiding the morbidity and mortality of treatment, we will also hopefully save costs as well,” she commented. So far, essentially all of the strategies for chemoprevention, other than sunscreen, involve KCs, which leaves a large unmet need for better ways to prevent melanoma. However, Dr. Hartman noted that KCs represent the most common type of cancer of any type.
Just days after Dr. Hartman spoke at the meeting, a prospective study of vitamin A that found an inverse association between vitamin A intake and cutaneous SCC risk was, in fact, published in JAMA Dermatology (2019 Jul 31. doi: 10.1001/jamadermatol.2019.1937).
Dr. Hartman reported no financial relationships relevant to her presentation.
EXPERT ANALYSIS FROM SUMMER AAD 2019
Trained interpreters essential for treating non–English-speaking patients
NEW YORK – Clinicians should resist the temptation to use untrained interpreters, such as a child, another relative, or their own limited language skills, when treating patients who cannot communicate in English, according to an expert reviewing this issue at the American Academy of Dermatology summer meeting.
In clinical encounters with patients who have limited English proficiency, “ reported Amy Y.Y. Chen, MD, who is affiliated with Central Connecticut Dermatology in Canton.
In many situations, interpreter services are required by law. This includes a provision of the 1963 Civil Rights Act that specifies these services should be made available to any individual with limited English proficiency receiving federal financial assistance (with the exception of Medicare Part B).
In reviewing this and other laws, Dr. Chen explained that many prohibitions are explicit. For example, it is against the law for clinicians to communicate with the patient through children, whether or not they are related to the patient. A patient’s adult companions are also prohibited from interpreting unless the patient has provided express permission.
Despite the rules, some clinicians might be tempted to forgo a translator when none is readily available, opting for an improvised solution. Dr. Chen said that this is ill advised even when it is not illegal.
“There are a lot of potential problems with using nonprofessional interpreters, starting with the issue of confidentiality,” Dr. Chen warned.
As defined by the Department of Health & Human Services, a qualified interpreter establishes competency by developing familiarity with specialized terminology; by communicating accurately, effectively, and impartially; and by recognizing the ethical issues, including confidentiality, essential to their role.
By itself, language fluency might not be sufficient. Many physicians have conversational fluency in one or more languages other than English, but Dr. Chen pointed out that complex and nuanced clinical descriptions might be difficult to follow for a nonnative speaker. Moreover, many individuals who have no problem posing questions in a foreign language don’t do nearly as well in following the answers.
As interpreters, family members can be particularly problematic. In addition to the issues of confidentiality and medical terminology, a family member might have his or her own agenda that influences how questions and answers are conveyed.
Moreover, family members and others untrained in translating might edit answers based on their own sense of relevance. Many clinicians working through an interpreter will recognize the experience of receiving a yes or no answer after a lengthy discussion between a nontrained interpreter and patient. In such situations, the clinician can reasonably worry that important information was lost.
Typically, major hospitals already offer a systematic approach to providing interpreters when needed, but physicians working in private practice or other smaller practice settings might not. According to Dr. Chen, who recently collaborated on review of this issue (J Am Acad Dermatol. 2019 Mar;80:829-31), they should.
Interpreter services are available by telephone or Internet. Fees typically fall in the range of $2-$5 per minute. In offices with bilingual staff members, formal medical interpreter training might make sense. The Certification Commission for Healthcare Interpreters and the National Board of Certification for Medical Interpreters can help in this process.
When using a medical interpreter, Dr. Chen had some tips.
“Maintain eye contact and talk to the patient,” said Dr. Chen, suggesting that the interpreter, if present in the room, be seated next to or behind the patient. Whether the interpreter is in the room or participating remotely, Dr. Chen advised against speaking through the interpreter with such phases as “tell her that.” Rather, she advised speaking directly to the patient with the interpreter providing the translation.
More practically, Dr. Chen recommended speaking slowly and posing only one question at a time. She also recommended strategies to elicit reassurance that the patient has understood what was communicated. Not least, she recommended a “show me” approach in which a patient can repeat or demonstrate what he or she has learned.
Citing evidence that poor and incomplete translation contributes to medical errors and patient dissatisfaction, Dr. Chen reiterated that engaging unbiased trained translators is advisable for good clinical care even if it were not mandated by law.
NEW YORK – Clinicians should resist the temptation to use untrained interpreters, such as a child, another relative, or their own limited language skills, when treating patients who cannot communicate in English, according to an expert reviewing this issue at the American Academy of Dermatology summer meeting.
In clinical encounters with patients who have limited English proficiency, “ reported Amy Y.Y. Chen, MD, who is affiliated with Central Connecticut Dermatology in Canton.
In many situations, interpreter services are required by law. This includes a provision of the 1963 Civil Rights Act that specifies these services should be made available to any individual with limited English proficiency receiving federal financial assistance (with the exception of Medicare Part B).
In reviewing this and other laws, Dr. Chen explained that many prohibitions are explicit. For example, it is against the law for clinicians to communicate with the patient through children, whether or not they are related to the patient. A patient’s adult companions are also prohibited from interpreting unless the patient has provided express permission.
Despite the rules, some clinicians might be tempted to forgo a translator when none is readily available, opting for an improvised solution. Dr. Chen said that this is ill advised even when it is not illegal.
“There are a lot of potential problems with using nonprofessional interpreters, starting with the issue of confidentiality,” Dr. Chen warned.
As defined by the Department of Health & Human Services, a qualified interpreter establishes competency by developing familiarity with specialized terminology; by communicating accurately, effectively, and impartially; and by recognizing the ethical issues, including confidentiality, essential to their role.
By itself, language fluency might not be sufficient. Many physicians have conversational fluency in one or more languages other than English, but Dr. Chen pointed out that complex and nuanced clinical descriptions might be difficult to follow for a nonnative speaker. Moreover, many individuals who have no problem posing questions in a foreign language don’t do nearly as well in following the answers.
As interpreters, family members can be particularly problematic. In addition to the issues of confidentiality and medical terminology, a family member might have his or her own agenda that influences how questions and answers are conveyed.
Moreover, family members and others untrained in translating might edit answers based on their own sense of relevance. Many clinicians working through an interpreter will recognize the experience of receiving a yes or no answer after a lengthy discussion between a nontrained interpreter and patient. In such situations, the clinician can reasonably worry that important information was lost.
Typically, major hospitals already offer a systematic approach to providing interpreters when needed, but physicians working in private practice or other smaller practice settings might not. According to Dr. Chen, who recently collaborated on review of this issue (J Am Acad Dermatol. 2019 Mar;80:829-31), they should.
Interpreter services are available by telephone or Internet. Fees typically fall in the range of $2-$5 per minute. In offices with bilingual staff members, formal medical interpreter training might make sense. The Certification Commission for Healthcare Interpreters and the National Board of Certification for Medical Interpreters can help in this process.
When using a medical interpreter, Dr. Chen had some tips.
“Maintain eye contact and talk to the patient,” said Dr. Chen, suggesting that the interpreter, if present in the room, be seated next to or behind the patient. Whether the interpreter is in the room or participating remotely, Dr. Chen advised against speaking through the interpreter with such phases as “tell her that.” Rather, she advised speaking directly to the patient with the interpreter providing the translation.
More practically, Dr. Chen recommended speaking slowly and posing only one question at a time. She also recommended strategies to elicit reassurance that the patient has understood what was communicated. Not least, she recommended a “show me” approach in which a patient can repeat or demonstrate what he or she has learned.
Citing evidence that poor and incomplete translation contributes to medical errors and patient dissatisfaction, Dr. Chen reiterated that engaging unbiased trained translators is advisable for good clinical care even if it were not mandated by law.
NEW YORK – Clinicians should resist the temptation to use untrained interpreters, such as a child, another relative, or their own limited language skills, when treating patients who cannot communicate in English, according to an expert reviewing this issue at the American Academy of Dermatology summer meeting.
In clinical encounters with patients who have limited English proficiency, “ reported Amy Y.Y. Chen, MD, who is affiliated with Central Connecticut Dermatology in Canton.
In many situations, interpreter services are required by law. This includes a provision of the 1963 Civil Rights Act that specifies these services should be made available to any individual with limited English proficiency receiving federal financial assistance (with the exception of Medicare Part B).
In reviewing this and other laws, Dr. Chen explained that many prohibitions are explicit. For example, it is against the law for clinicians to communicate with the patient through children, whether or not they are related to the patient. A patient’s adult companions are also prohibited from interpreting unless the patient has provided express permission.
Despite the rules, some clinicians might be tempted to forgo a translator when none is readily available, opting for an improvised solution. Dr. Chen said that this is ill advised even when it is not illegal.
“There are a lot of potential problems with using nonprofessional interpreters, starting with the issue of confidentiality,” Dr. Chen warned.
As defined by the Department of Health & Human Services, a qualified interpreter establishes competency by developing familiarity with specialized terminology; by communicating accurately, effectively, and impartially; and by recognizing the ethical issues, including confidentiality, essential to their role.
By itself, language fluency might not be sufficient. Many physicians have conversational fluency in one or more languages other than English, but Dr. Chen pointed out that complex and nuanced clinical descriptions might be difficult to follow for a nonnative speaker. Moreover, many individuals who have no problem posing questions in a foreign language don’t do nearly as well in following the answers.
As interpreters, family members can be particularly problematic. In addition to the issues of confidentiality and medical terminology, a family member might have his or her own agenda that influences how questions and answers are conveyed.
Moreover, family members and others untrained in translating might edit answers based on their own sense of relevance. Many clinicians working through an interpreter will recognize the experience of receiving a yes or no answer after a lengthy discussion between a nontrained interpreter and patient. In such situations, the clinician can reasonably worry that important information was lost.
Typically, major hospitals already offer a systematic approach to providing interpreters when needed, but physicians working in private practice or other smaller practice settings might not. According to Dr. Chen, who recently collaborated on review of this issue (J Am Acad Dermatol. 2019 Mar;80:829-31), they should.
Interpreter services are available by telephone or Internet. Fees typically fall in the range of $2-$5 per minute. In offices with bilingual staff members, formal medical interpreter training might make sense. The Certification Commission for Healthcare Interpreters and the National Board of Certification for Medical Interpreters can help in this process.
When using a medical interpreter, Dr. Chen had some tips.
“Maintain eye contact and talk to the patient,” said Dr. Chen, suggesting that the interpreter, if present in the room, be seated next to or behind the patient. Whether the interpreter is in the room or participating remotely, Dr. Chen advised against speaking through the interpreter with such phases as “tell her that.” Rather, she advised speaking directly to the patient with the interpreter providing the translation.
More practically, Dr. Chen recommended speaking slowly and posing only one question at a time. She also recommended strategies to elicit reassurance that the patient has understood what was communicated. Not least, she recommended a “show me” approach in which a patient can repeat or demonstrate what he or she has learned.
Citing evidence that poor and incomplete translation contributes to medical errors and patient dissatisfaction, Dr. Chen reiterated that engaging unbiased trained translators is advisable for good clinical care even if it were not mandated by law.
EXPERT ANALYSIS FROM SUMMER AAD 2019
Dermatitis associated with surgical implants merits conservative approach
NEW YORK – In patients who develop dermatitis after implantation of a device containing materials to which they have a contact allergy, explantation is not necessarily a cure for their symptoms.
“It can be difficult to predict who will or will not clear when the device is removed. In addition, in some cases device explantation could lead to other issues,” cautioned Ari M. Goldminz, MD, a dermatologist at Brigham and Women’s Hospital, Boston, MA. “Offering non-surgical options and a thorough investigation of other potential causes unrelated to the implant may provide a path to avoid explantation.” However, for other patients removal of the device might be the preferred option.
During his presentation at the American Academy of Dermatology summer meeting, he described illustrative cases. These patients developed dermatitis within weeks or months after receiving a surgical implant, and tested positive for a material that was in the implanted device.
In one of these cases, the suspected problem was a metal plate containing chromium that was placed during an orthopedic repair. Subsequent patch testing revealed a reaction to chromium and the implant was eventually removed.
However, there was no improvement in dermatitis following removal of the metal plate.
“The symptoms ultimately improved after starting on a low-chromium diet and avoiding other allergens identified on patch testing, such as those found in skin care products,” Dr. Goldminz explained. He does not discount the role that the implant may have played in the onset of dermatitis,, but improvement required avoidance strategies other than device explantation.
There are studies suggesting that patch testing prior to surgery can help certain patients and surgeons select implant materials, such as when patients have a clinical history of metal sensitivity (Arch Dermatol. 2012 Jun;148[6]:687-93). However, other studies have also found that positive patch test results do not necessarily predict outcomes following surgery (J Arthroplasty. 2016 Aug;31[8]1717-21).
Although it might make sense to consider pre-operative patch testing in patients with a clinical history of rashes from metallic objects, Dr. Goldminz indicated that some patients might still need to weigh the benefits of the implant against the risks of a hypersensitivity reaction when no devices free of the allergen are available.
“In certain cases, patients might decide the risk-to-benefit ratio favors the device depending on factors such as the indication for the surgery, alternative options available, and what device removal might involve,” Dr. Goldminz said. Additionally, when patients develop rashes thought to be related to materials present in an implanted device, there are also medical treatments that can be considered if device explantation is not preferred or if it is an impractical approach.
NEW YORK – In patients who develop dermatitis after implantation of a device containing materials to which they have a contact allergy, explantation is not necessarily a cure for their symptoms.
“It can be difficult to predict who will or will not clear when the device is removed. In addition, in some cases device explantation could lead to other issues,” cautioned Ari M. Goldminz, MD, a dermatologist at Brigham and Women’s Hospital, Boston, MA. “Offering non-surgical options and a thorough investigation of other potential causes unrelated to the implant may provide a path to avoid explantation.” However, for other patients removal of the device might be the preferred option.
During his presentation at the American Academy of Dermatology summer meeting, he described illustrative cases. These patients developed dermatitis within weeks or months after receiving a surgical implant, and tested positive for a material that was in the implanted device.
In one of these cases, the suspected problem was a metal plate containing chromium that was placed during an orthopedic repair. Subsequent patch testing revealed a reaction to chromium and the implant was eventually removed.
However, there was no improvement in dermatitis following removal of the metal plate.
“The symptoms ultimately improved after starting on a low-chromium diet and avoiding other allergens identified on patch testing, such as those found in skin care products,” Dr. Goldminz explained. He does not discount the role that the implant may have played in the onset of dermatitis,, but improvement required avoidance strategies other than device explantation.
There are studies suggesting that patch testing prior to surgery can help certain patients and surgeons select implant materials, such as when patients have a clinical history of metal sensitivity (Arch Dermatol. 2012 Jun;148[6]:687-93). However, other studies have also found that positive patch test results do not necessarily predict outcomes following surgery (J Arthroplasty. 2016 Aug;31[8]1717-21).
Although it might make sense to consider pre-operative patch testing in patients with a clinical history of rashes from metallic objects, Dr. Goldminz indicated that some patients might still need to weigh the benefits of the implant against the risks of a hypersensitivity reaction when no devices free of the allergen are available.
“In certain cases, patients might decide the risk-to-benefit ratio favors the device depending on factors such as the indication for the surgery, alternative options available, and what device removal might involve,” Dr. Goldminz said. Additionally, when patients develop rashes thought to be related to materials present in an implanted device, there are also medical treatments that can be considered if device explantation is not preferred or if it is an impractical approach.
NEW YORK – In patients who develop dermatitis after implantation of a device containing materials to which they have a contact allergy, explantation is not necessarily a cure for their symptoms.
“It can be difficult to predict who will or will not clear when the device is removed. In addition, in some cases device explantation could lead to other issues,” cautioned Ari M. Goldminz, MD, a dermatologist at Brigham and Women’s Hospital, Boston, MA. “Offering non-surgical options and a thorough investigation of other potential causes unrelated to the implant may provide a path to avoid explantation.” However, for other patients removal of the device might be the preferred option.
During his presentation at the American Academy of Dermatology summer meeting, he described illustrative cases. These patients developed dermatitis within weeks or months after receiving a surgical implant, and tested positive for a material that was in the implanted device.
In one of these cases, the suspected problem was a metal plate containing chromium that was placed during an orthopedic repair. Subsequent patch testing revealed a reaction to chromium and the implant was eventually removed.
However, there was no improvement in dermatitis following removal of the metal plate.
“The symptoms ultimately improved after starting on a low-chromium diet and avoiding other allergens identified on patch testing, such as those found in skin care products,” Dr. Goldminz explained. He does not discount the role that the implant may have played in the onset of dermatitis,, but improvement required avoidance strategies other than device explantation.
There are studies suggesting that patch testing prior to surgery can help certain patients and surgeons select implant materials, such as when patients have a clinical history of metal sensitivity (Arch Dermatol. 2012 Jun;148[6]:687-93). However, other studies have also found that positive patch test results do not necessarily predict outcomes following surgery (J Arthroplasty. 2016 Aug;31[8]1717-21).
Although it might make sense to consider pre-operative patch testing in patients with a clinical history of rashes from metallic objects, Dr. Goldminz indicated that some patients might still need to weigh the benefits of the implant against the risks of a hypersensitivity reaction when no devices free of the allergen are available.
“In certain cases, patients might decide the risk-to-benefit ratio favors the device depending on factors such as the indication for the surgery, alternative options available, and what device removal might involve,” Dr. Goldminz said. Additionally, when patients develop rashes thought to be related to materials present in an implanted device, there are also medical treatments that can be considered if device explantation is not preferred or if it is an impractical approach.
REPORTING FROM SUMMER AAD 2019
After prior TNFi in axSpA, taking secukinumab or another TNFi appear equivalent
MADRID – In axial spondyloarthritis patients who discontinue a tumor necrosis factor inhibitor (TNFi), there does not appear to be any advantage for using the anti–interleukin-17 biologic secukinumab over a different tumor necrosis factor inhibitor for next therapy, according to an analysis presented at the European Congress of Rheumatology.
“Switching to secukinumab [Cosentyx] might even be inferior in many patients,” according to Adrian Ciurea, MD, of the clinic for rheumatology at University Hospital Zürich.
This conclusion was reached in a retrospective analysis of axial spondyloarthritis (axSpA) patients enrolled in the Swiss Clinical Quality Management Cohort. Although Dr. Ciurea said that a prospective trial is needed to confirm the findings, this study was conducted because there have been, up until now, “no data to choose between options” to guide this choice.
In this study of 382 axSpA patients who were candidates for a new biologic after discontinuing a previous TNFi, 275 were started on a different TNFi and 107 were started on secukinumab. Although about 60% of patients in both groups were HLAB27-positive, there were many other characteristics, including those related to disease severity, that were different, Dr. Ciurea acknowledged.
Specifically, the proportion of patients starting secukinumab treated with two or more TNF inhibitors was greater than that of patients switching to another TNFi (77.6% vs. 37.8%; P less than .001). In addition, patients in the secukinumab group had a higher baseline disease activity, more enthesitis, and greater axial impairment.
These were reflected in higher average Bath Ankylosing Spondylitis Disease Activity Index scores (6.1 vs. 4.8; P less than .001) as well as other baseline clinical scoring methods, such as the Bath Ankylosing Spondylitis Functional Index and the Maastricht Ankylosing Spondylitis Enthesitis Score.
However, baseline high-sensitivity C-reactive protein levels, number of swollen joints, or years of symptom duration were not significantly different between the groups, although all were numerically higher in the secukinumab group. The proportion of patients with uveitis was higher in the TNFi group. About 70% of patients in both groups had discontinued their prior TNFi for inadequate response.
For the primary assessment of drug survival on the new therapy, the median time was 1.1 years in the secukinumab group and 2.0 years in the group switched to a new TNFi, without adjustment for baseline characteristics and disease severity. After risk adjustment, this difference was no statistically significant.
“There was an interaction with gender, indicating a significantly higher risk of discontinuing secukinumab than a new TNFi in men,” according to Dr. Ciurea. This was not seen in women.
Previous studies have shown the response rate to a second TNFi is typically lower than for an initial TNFi therapy. Previous studies have also shown that response to secukinumab is lower in patients with previous TNFi experience than in those who are naive to biologics, Dr. Ciurea said. This analysis suggests that the likelihood of sustained disease control is not greater in TNFi-experienced patients who start secukinumab relative to a different TNFi.
When asked if the data had been analyzed to compare response in patients exposed to only one prior TNFi, Dr. Ciurea replied that this could not be done because the sample size was too small.
Although Dr. Ciurea acknowledged the limitations of retrospective studies with risk adjustments, he concluded that there does not appear to be an advantage for initiating secukinumab over starting a different TNFi in axSpA patients who require a switch from their current TNFi,
Even though he said that this is the first study to address this question objectively, Dr. Ciurea said, “A sufficiently powered, prospective, head-to-head trial is needed.”
Dr. Ciurea reported multiple financial relationships with pharmaceutical companies but received no funding for this study.
SOURCE: Tellenbach C et al. Ann Rheum Dis. 2019;78(Suppl 2):197. Abstract OPO237, doi: 10.1136/annrheumdis-2019-eular.2427
MADRID – In axial spondyloarthritis patients who discontinue a tumor necrosis factor inhibitor (TNFi), there does not appear to be any advantage for using the anti–interleukin-17 biologic secukinumab over a different tumor necrosis factor inhibitor for next therapy, according to an analysis presented at the European Congress of Rheumatology.
“Switching to secukinumab [Cosentyx] might even be inferior in many patients,” according to Adrian Ciurea, MD, of the clinic for rheumatology at University Hospital Zürich.
This conclusion was reached in a retrospective analysis of axial spondyloarthritis (axSpA) patients enrolled in the Swiss Clinical Quality Management Cohort. Although Dr. Ciurea said that a prospective trial is needed to confirm the findings, this study was conducted because there have been, up until now, “no data to choose between options” to guide this choice.
In this study of 382 axSpA patients who were candidates for a new biologic after discontinuing a previous TNFi, 275 were started on a different TNFi and 107 were started on secukinumab. Although about 60% of patients in both groups were HLAB27-positive, there were many other characteristics, including those related to disease severity, that were different, Dr. Ciurea acknowledged.
Specifically, the proportion of patients starting secukinumab treated with two or more TNF inhibitors was greater than that of patients switching to another TNFi (77.6% vs. 37.8%; P less than .001). In addition, patients in the secukinumab group had a higher baseline disease activity, more enthesitis, and greater axial impairment.
These were reflected in higher average Bath Ankylosing Spondylitis Disease Activity Index scores (6.1 vs. 4.8; P less than .001) as well as other baseline clinical scoring methods, such as the Bath Ankylosing Spondylitis Functional Index and the Maastricht Ankylosing Spondylitis Enthesitis Score.
However, baseline high-sensitivity C-reactive protein levels, number of swollen joints, or years of symptom duration were not significantly different between the groups, although all were numerically higher in the secukinumab group. The proportion of patients with uveitis was higher in the TNFi group. About 70% of patients in both groups had discontinued their prior TNFi for inadequate response.
For the primary assessment of drug survival on the new therapy, the median time was 1.1 years in the secukinumab group and 2.0 years in the group switched to a new TNFi, without adjustment for baseline characteristics and disease severity. After risk adjustment, this difference was no statistically significant.
“There was an interaction with gender, indicating a significantly higher risk of discontinuing secukinumab than a new TNFi in men,” according to Dr. Ciurea. This was not seen in women.
Previous studies have shown the response rate to a second TNFi is typically lower than for an initial TNFi therapy. Previous studies have also shown that response to secukinumab is lower in patients with previous TNFi experience than in those who are naive to biologics, Dr. Ciurea said. This analysis suggests that the likelihood of sustained disease control is not greater in TNFi-experienced patients who start secukinumab relative to a different TNFi.
When asked if the data had been analyzed to compare response in patients exposed to only one prior TNFi, Dr. Ciurea replied that this could not be done because the sample size was too small.
Although Dr. Ciurea acknowledged the limitations of retrospective studies with risk adjustments, he concluded that there does not appear to be an advantage for initiating secukinumab over starting a different TNFi in axSpA patients who require a switch from their current TNFi,
Even though he said that this is the first study to address this question objectively, Dr. Ciurea said, “A sufficiently powered, prospective, head-to-head trial is needed.”
Dr. Ciurea reported multiple financial relationships with pharmaceutical companies but received no funding for this study.
SOURCE: Tellenbach C et al. Ann Rheum Dis. 2019;78(Suppl 2):197. Abstract OPO237, doi: 10.1136/annrheumdis-2019-eular.2427
MADRID – In axial spondyloarthritis patients who discontinue a tumor necrosis factor inhibitor (TNFi), there does not appear to be any advantage for using the anti–interleukin-17 biologic secukinumab over a different tumor necrosis factor inhibitor for next therapy, according to an analysis presented at the European Congress of Rheumatology.
“Switching to secukinumab [Cosentyx] might even be inferior in many patients,” according to Adrian Ciurea, MD, of the clinic for rheumatology at University Hospital Zürich.
This conclusion was reached in a retrospective analysis of axial spondyloarthritis (axSpA) patients enrolled in the Swiss Clinical Quality Management Cohort. Although Dr. Ciurea said that a prospective trial is needed to confirm the findings, this study was conducted because there have been, up until now, “no data to choose between options” to guide this choice.
In this study of 382 axSpA patients who were candidates for a new biologic after discontinuing a previous TNFi, 275 were started on a different TNFi and 107 were started on secukinumab. Although about 60% of patients in both groups were HLAB27-positive, there were many other characteristics, including those related to disease severity, that were different, Dr. Ciurea acknowledged.
Specifically, the proportion of patients starting secukinumab treated with two or more TNF inhibitors was greater than that of patients switching to another TNFi (77.6% vs. 37.8%; P less than .001). In addition, patients in the secukinumab group had a higher baseline disease activity, more enthesitis, and greater axial impairment.
These were reflected in higher average Bath Ankylosing Spondylitis Disease Activity Index scores (6.1 vs. 4.8; P less than .001) as well as other baseline clinical scoring methods, such as the Bath Ankylosing Spondylitis Functional Index and the Maastricht Ankylosing Spondylitis Enthesitis Score.
However, baseline high-sensitivity C-reactive protein levels, number of swollen joints, or years of symptom duration were not significantly different between the groups, although all were numerically higher in the secukinumab group. The proportion of patients with uveitis was higher in the TNFi group. About 70% of patients in both groups had discontinued their prior TNFi for inadequate response.
For the primary assessment of drug survival on the new therapy, the median time was 1.1 years in the secukinumab group and 2.0 years in the group switched to a new TNFi, without adjustment for baseline characteristics and disease severity. After risk adjustment, this difference was no statistically significant.
“There was an interaction with gender, indicating a significantly higher risk of discontinuing secukinumab than a new TNFi in men,” according to Dr. Ciurea. This was not seen in women.
Previous studies have shown the response rate to a second TNFi is typically lower than for an initial TNFi therapy. Previous studies have also shown that response to secukinumab is lower in patients with previous TNFi experience than in those who are naive to biologics, Dr. Ciurea said. This analysis suggests that the likelihood of sustained disease control is not greater in TNFi-experienced patients who start secukinumab relative to a different TNFi.
When asked if the data had been analyzed to compare response in patients exposed to only one prior TNFi, Dr. Ciurea replied that this could not be done because the sample size was too small.
Although Dr. Ciurea acknowledged the limitations of retrospective studies with risk adjustments, he concluded that there does not appear to be an advantage for initiating secukinumab over starting a different TNFi in axSpA patients who require a switch from their current TNFi,
Even though he said that this is the first study to address this question objectively, Dr. Ciurea said, “A sufficiently powered, prospective, head-to-head trial is needed.”
Dr. Ciurea reported multiple financial relationships with pharmaceutical companies but received no funding for this study.
SOURCE: Tellenbach C et al. Ann Rheum Dis. 2019;78(Suppl 2):197. Abstract OPO237, doi: 10.1136/annrheumdis-2019-eular.2427
REPORTING FROM EULAR 2019 CONGRESS
New analysis challenges fluid resuscitation guidelines for patients in shock
Although guideline recommended, according to a detailed analysis of available data, including a randomized trial.
Several sets of guidelines for resuscitation of patients in shock have advocated volume expansion with bolus intravenous fluid, but that recommendation was based on expected physiologic benefits not a randomized trial. The only randomized trial associated this approach showed increased mortality, and a new analysis of these and other data appears to explain why.
According to the findings of a study lead by Michael Levin, MD, of the department of medicine at Imperial College London and colleagues, “volume resuscitation is associated with deterioration of respiratory function and neurological function in some patients.” Their study was published in Lancet Respiratory Medicine. The authors stated that saline-induced hyperchloremic acidosis appears to have been “a major contributor” to the observed increase in adverse outcomes.
The key take home message is that “normal saline and other unbuffered crystalloid solutions should be avoided in resuscitating seriously ill patients,” according to the authors, who believe the findings might be relevant to adults as well as children.
The controversy about the role of volume expansion for management of shock was ignited by a 2011 trial called FEAST (N Engl J Med. 2011;364:2483-95). That trial, which randomized African children with severe febrile illness to a bolus of 20-40 mg of 5% albumin solution, a bolus of 0.9% saline solution, or no bolus, was halted early when 48-hour mortality data showed a lower death rate in the no bolus group (7.3%) than either the albumin (10.6%) or saline (10.5%) bolus groups.
The FEAST result was unexpected and so contrary to accepted thinking that it prompted widespread debate, including whether findings in the resource-poor area of the world where the FEAST trial was conducted could be extrapolated to centers elsewhere in the world. Arguing for benefit, fluid resuscitation is known to increase pulse pressure and urinary output. Arguing against benefit, pulmonary edema is a known complication of bolus fluid replacement.
In an attempt to address and potentially resolve this controversy, data collected in the FEAST trial along with four other sets of data involving volume expansion in critically ill children were evaluated with a focus on changes in cardiovascular, neurological, and respiratory function. Analysis of blood biochemistry and blood oxygen transport were also conducted.
The cardiovascular, respiratory, and neurologic functions were scored on the basis of objective measurements, such as heart rate, respiratory rate, and blood pressure. These measures were evaluated prior to fluid administration and at 1 hour, 4 hours, 8 hours, 24 hours, and 48 hours after fluid administration. Odds ratio (OR) of an adverse outcome were evaluated in the context of each 10-unit change in these scores.
Relative to baseline, there was worsening respiratory and neurological function after fluid administration. Although cardiovascular function improved, hemoglobin concentrations were lower in those who received fluid than in those who did not. Fluid resuscitation was also associated with lower bicarbonate and increased base deficit and chloride at 24 hours.
Regression modeling with physiological variables suggests “that the increased mortality in FEAST can be explained by bolus-induced worsening in respiratory and neurological function, hemodilution, and hyperchloremic acidosis,” according to the authors.
Analyses of the four other sets of data, which included children treated for meningococcal sepsis in the United Kingdom, acutely ill with malaria treated in Malawi, and cohorts of children in South Africa and a London hospital for acute illnesses, provided supportive data.
Although this analysis does not address the value of administering buffered solutions in low volumes, the authors concluded that the data from the FEAST trial are generalizable. They challenge the routine use of bolus infusions of saline or albumin in the initial management of shock, which has been guideline recommended. The risks of fluid resuscitation might be particularly high among children who already have compromised respiratory or neurologic function.
SOURCE: Levin M et al. Lancet Respir Med. 2019;7:581-93.
Although guideline recommended, according to a detailed analysis of available data, including a randomized trial.
Several sets of guidelines for resuscitation of patients in shock have advocated volume expansion with bolus intravenous fluid, but that recommendation was based on expected physiologic benefits not a randomized trial. The only randomized trial associated this approach showed increased mortality, and a new analysis of these and other data appears to explain why.
According to the findings of a study lead by Michael Levin, MD, of the department of medicine at Imperial College London and colleagues, “volume resuscitation is associated with deterioration of respiratory function and neurological function in some patients.” Their study was published in Lancet Respiratory Medicine. The authors stated that saline-induced hyperchloremic acidosis appears to have been “a major contributor” to the observed increase in adverse outcomes.
The key take home message is that “normal saline and other unbuffered crystalloid solutions should be avoided in resuscitating seriously ill patients,” according to the authors, who believe the findings might be relevant to adults as well as children.
The controversy about the role of volume expansion for management of shock was ignited by a 2011 trial called FEAST (N Engl J Med. 2011;364:2483-95). That trial, which randomized African children with severe febrile illness to a bolus of 20-40 mg of 5% albumin solution, a bolus of 0.9% saline solution, or no bolus, was halted early when 48-hour mortality data showed a lower death rate in the no bolus group (7.3%) than either the albumin (10.6%) or saline (10.5%) bolus groups.
The FEAST result was unexpected and so contrary to accepted thinking that it prompted widespread debate, including whether findings in the resource-poor area of the world where the FEAST trial was conducted could be extrapolated to centers elsewhere in the world. Arguing for benefit, fluid resuscitation is known to increase pulse pressure and urinary output. Arguing against benefit, pulmonary edema is a known complication of bolus fluid replacement.
In an attempt to address and potentially resolve this controversy, data collected in the FEAST trial along with four other sets of data involving volume expansion in critically ill children were evaluated with a focus on changes in cardiovascular, neurological, and respiratory function. Analysis of blood biochemistry and blood oxygen transport were also conducted.
The cardiovascular, respiratory, and neurologic functions were scored on the basis of objective measurements, such as heart rate, respiratory rate, and blood pressure. These measures were evaluated prior to fluid administration and at 1 hour, 4 hours, 8 hours, 24 hours, and 48 hours after fluid administration. Odds ratio (OR) of an adverse outcome were evaluated in the context of each 10-unit change in these scores.
Relative to baseline, there was worsening respiratory and neurological function after fluid administration. Although cardiovascular function improved, hemoglobin concentrations were lower in those who received fluid than in those who did not. Fluid resuscitation was also associated with lower bicarbonate and increased base deficit and chloride at 24 hours.
Regression modeling with physiological variables suggests “that the increased mortality in FEAST can be explained by bolus-induced worsening in respiratory and neurological function, hemodilution, and hyperchloremic acidosis,” according to the authors.
Analyses of the four other sets of data, which included children treated for meningococcal sepsis in the United Kingdom, acutely ill with malaria treated in Malawi, and cohorts of children in South Africa and a London hospital for acute illnesses, provided supportive data.
Although this analysis does not address the value of administering buffered solutions in low volumes, the authors concluded that the data from the FEAST trial are generalizable. They challenge the routine use of bolus infusions of saline or albumin in the initial management of shock, which has been guideline recommended. The risks of fluid resuscitation might be particularly high among children who already have compromised respiratory or neurologic function.
SOURCE: Levin M et al. Lancet Respir Med. 2019;7:581-93.
Although guideline recommended, according to a detailed analysis of available data, including a randomized trial.
Several sets of guidelines for resuscitation of patients in shock have advocated volume expansion with bolus intravenous fluid, but that recommendation was based on expected physiologic benefits not a randomized trial. The only randomized trial associated this approach showed increased mortality, and a new analysis of these and other data appears to explain why.
According to the findings of a study lead by Michael Levin, MD, of the department of medicine at Imperial College London and colleagues, “volume resuscitation is associated with deterioration of respiratory function and neurological function in some patients.” Their study was published in Lancet Respiratory Medicine. The authors stated that saline-induced hyperchloremic acidosis appears to have been “a major contributor” to the observed increase in adverse outcomes.
The key take home message is that “normal saline and other unbuffered crystalloid solutions should be avoided in resuscitating seriously ill patients,” according to the authors, who believe the findings might be relevant to adults as well as children.
The controversy about the role of volume expansion for management of shock was ignited by a 2011 trial called FEAST (N Engl J Med. 2011;364:2483-95). That trial, which randomized African children with severe febrile illness to a bolus of 20-40 mg of 5% albumin solution, a bolus of 0.9% saline solution, or no bolus, was halted early when 48-hour mortality data showed a lower death rate in the no bolus group (7.3%) than either the albumin (10.6%) or saline (10.5%) bolus groups.
The FEAST result was unexpected and so contrary to accepted thinking that it prompted widespread debate, including whether findings in the resource-poor area of the world where the FEAST trial was conducted could be extrapolated to centers elsewhere in the world. Arguing for benefit, fluid resuscitation is known to increase pulse pressure and urinary output. Arguing against benefit, pulmonary edema is a known complication of bolus fluid replacement.
In an attempt to address and potentially resolve this controversy, data collected in the FEAST trial along with four other sets of data involving volume expansion in critically ill children were evaluated with a focus on changes in cardiovascular, neurological, and respiratory function. Analysis of blood biochemistry and blood oxygen transport were also conducted.
The cardiovascular, respiratory, and neurologic functions were scored on the basis of objective measurements, such as heart rate, respiratory rate, and blood pressure. These measures were evaluated prior to fluid administration and at 1 hour, 4 hours, 8 hours, 24 hours, and 48 hours after fluid administration. Odds ratio (OR) of an adverse outcome were evaluated in the context of each 10-unit change in these scores.
Relative to baseline, there was worsening respiratory and neurological function after fluid administration. Although cardiovascular function improved, hemoglobin concentrations were lower in those who received fluid than in those who did not. Fluid resuscitation was also associated with lower bicarbonate and increased base deficit and chloride at 24 hours.
Regression modeling with physiological variables suggests “that the increased mortality in FEAST can be explained by bolus-induced worsening in respiratory and neurological function, hemodilution, and hyperchloremic acidosis,” according to the authors.
Analyses of the four other sets of data, which included children treated for meningococcal sepsis in the United Kingdom, acutely ill with malaria treated in Malawi, and cohorts of children in South Africa and a London hospital for acute illnesses, provided supportive data.
Although this analysis does not address the value of administering buffered solutions in low volumes, the authors concluded that the data from the FEAST trial are generalizable. They challenge the routine use of bolus infusions of saline or albumin in the initial management of shock, which has been guideline recommended. The risks of fluid resuscitation might be particularly high among children who already have compromised respiratory or neurologic function.
SOURCE: Levin M et al. Lancet Respir Med. 2019;7:581-93.
FROM THE LANCET RESPIRATORY MEDICINE
Flurry of new anti–IL-17 monoclonal antibodies show efficacy in axSpA
MADRID – Trial results presented at the European Congress of Rheumatology for three anti–interleukin-17 receptor monoclonal antibodies under investigation for the treatment of axial spondyloarthritis (axSpA), including one for ankylosing spondylitis (AS), appear to support further clinical development and regulatory review to potentially join secukinumab (Cosentyx) and ixekizumab (Taltz) as the only IL-17 inhibitors to be licensed for rheumatic diseases.
Both netakimab and brodalumab (Siliq) achieved positive results in separate phase 3 trials for the treatment of axSpA, while new data from a phase 2b trial of bimekizumab was associated with improvement in the quality of life of patients with AS. Brodalumab is already approved by the Food and Drug Administration for treating moderate to severe plaque psoriasis.
Netakimab
The multinational, double-blind, phase 3 trial with netakimab, called the ASTERA trial, randomized 228 patients with radiographic axSpA to either 120 mg of the experimental agent or placebo, each administered subcutaneously in weekly doses in the first 2 weeks and then every other week thereafter. The primary endpoint was a 40% improvement in Assessment of SpondyloArthritis International Society response criteria (ASAS40) at week 16.
A larger proportion of patients in the netakimab arm met the primary endpoint, compared with those in the placebo arm (40.4% vs. 2.63%, respectively; P less than .0001), reported Inna Gaydukova, MD, of Mechnikov North-Western State Medical University, St. Petersburg, Russia.
“Most of the secondary efficacy endpoints also showed a significant advantage for netakimab relative to placebo by week 4, and these advantages remained significant for the remainder of the study,” she said.
The one serious adverse event in the study occurred in the placebo arm. Although mild to moderate anemia and neutropenia were associated with treatment, the drug was well tolerated overall.
“We did observe a significant reduction in inflammatory activity in the spine with MRI at week 16,” Dr. Gaydukova added. Functional improvements in the experimental arm relative to the placebo arm were also observed, although Dr. Gaydukova acknowledged that longer trials are needed to show that these benefits are durable.
Brodalumab
The results of a multinational, double-blind, phase 3 trial with brodalumab proved similar to those with netakimab. Conducted in Taiwan, Japan, and South Korea, the trial randomized 159 patients to 210 mg of brodalumab or placebo administered subcutaneously. The therapies were administered on the same schedule as in the netakimab trial. The primary outcome was also the same.
At week 16, 43.8% of those on the experimental agent versus 24.1% of those randomized to placebo achieved ASAS40 (P = .018). As in the netakimab study, greater activity with brodalumab than placebo was also seen on several secondary outcomes, such as ASAS20 (67.5% vs. 41.8%).
“In a subgroup analysis, there was an advantage for brodalumab over placebo whether or not patients had prior experience with a TNF [tumor necrosis factor] inhibitor, regardless of baseline hs-CRP [high sensitivity C-reactive protein] level and independent of HLA type,” reported James Cheng-Chung Wei, MD, of Chung Shan Medical University Hospital, Taichung, Taiwan.
There were no significant differences in the types or rates of adverse events, including serious adverse events, in patients assigned to brodalumab relative to placebo. Suicide ideation, which has been associated with some biologics targeting other immunologic mediators, was evaluated but not seen.
“We think brodalumab has the potential to be a new therapeutic option in axSpA,” said Dr. Wei, who reported that studies in AS are also planned.
Bimekizumab
Additional 12-week outcome data from the multinational, double-blind, phase 2b BE AGILE trial of bimekizumab in patients with active AS were presented by Désirée van der Heijde, MD, PhD, of Leiden (the Netherlands) University Medical Center.
Unlike secukinumab and most of the other anti–IL-17 receptor monoclonal antibodies in development, bimekizumab inhibits IL-17F in addition to IL-17A, according to Dr. van der Heijde. She cited experimental evidence suggesting that inhibition of both forms of IL-17 results in greater anti-inflammatory response.
In the initial and previously reported data from this dose-ranging study of 303 AS patients, all four doses of bimekizumab (16 mg, 64 mg, 160 mg, or 320 mg) were superior to placebo for the primary endpoint of ASAS40. However, greater relative benefit was observed for the three highest doses.
In the new analysis, symptoms were evaluated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). At 12 weeks, 47.5% of patients on the highest dose of bimekizumab versus only 11.9% of patients randomized to placebo achieved a 50% or greater level of improvement on the BASDAI, called BASDAI 50 (P less than .001).
The greater clinical activity of bimekizumab relative to placebo translated into improvement from baseline in Ankylosing Spondylitis Quality of Life scores. Greater reductions in Ankylosing Spondylitis Quality of Life scores relative to placebo, signaling an improved quality of life, were achieved with all doses, but they reached 4.6 points for the highest dose versus only 1.3 for placebo.
When evaluated with Patient Global Assessment of Disease Activity, another tool that reflects perception of disease burden, the score reduction was 3.3 points for the highest dose versus 1.0 points for placebo. Dr. van der Heijde characterized the reductions at the highest doses versus placebo as “significant” although she did not provide P values.
Like the data presented on the other newer anti–IL-17 therapies, bimekizumab was well tolerated with relatively low rates of adverse events, most of which were mild to moderate in severity, according to Dr. van der Heijde.
“The data from the BE AGILE trial supports phase 3 development in AS,” Dr. van der Heijde said. She noted that trials are also being planned in axSpA.
All three presenting authors reported multiple financial relationships with pharmaceutical companies, including, in each case, the pharmaceutical company that sponsored the trial they presented.
SOURCES: Gaydukova I et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):193-4, Abstract OP0232. doi: 10.1136/annrheumdis-2019-eular.6633; Wei JC et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):195, Abstract OP0234. doi: 10.1136/annrheumdis-2019-eular.6888; van der Heijde D et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):193, Abstract OP0231. doi: 10.1136/annrheumdis-2019-eular.6607.
MADRID – Trial results presented at the European Congress of Rheumatology for three anti–interleukin-17 receptor monoclonal antibodies under investigation for the treatment of axial spondyloarthritis (axSpA), including one for ankylosing spondylitis (AS), appear to support further clinical development and regulatory review to potentially join secukinumab (Cosentyx) and ixekizumab (Taltz) as the only IL-17 inhibitors to be licensed for rheumatic diseases.
Both netakimab and brodalumab (Siliq) achieved positive results in separate phase 3 trials for the treatment of axSpA, while new data from a phase 2b trial of bimekizumab was associated with improvement in the quality of life of patients with AS. Brodalumab is already approved by the Food and Drug Administration for treating moderate to severe plaque psoriasis.
Netakimab
The multinational, double-blind, phase 3 trial with netakimab, called the ASTERA trial, randomized 228 patients with radiographic axSpA to either 120 mg of the experimental agent or placebo, each administered subcutaneously in weekly doses in the first 2 weeks and then every other week thereafter. The primary endpoint was a 40% improvement in Assessment of SpondyloArthritis International Society response criteria (ASAS40) at week 16.
A larger proportion of patients in the netakimab arm met the primary endpoint, compared with those in the placebo arm (40.4% vs. 2.63%, respectively; P less than .0001), reported Inna Gaydukova, MD, of Mechnikov North-Western State Medical University, St. Petersburg, Russia.
“Most of the secondary efficacy endpoints also showed a significant advantage for netakimab relative to placebo by week 4, and these advantages remained significant for the remainder of the study,” she said.
The one serious adverse event in the study occurred in the placebo arm. Although mild to moderate anemia and neutropenia were associated with treatment, the drug was well tolerated overall.
“We did observe a significant reduction in inflammatory activity in the spine with MRI at week 16,” Dr. Gaydukova added. Functional improvements in the experimental arm relative to the placebo arm were also observed, although Dr. Gaydukova acknowledged that longer trials are needed to show that these benefits are durable.
Brodalumab
The results of a multinational, double-blind, phase 3 trial with brodalumab proved similar to those with netakimab. Conducted in Taiwan, Japan, and South Korea, the trial randomized 159 patients to 210 mg of brodalumab or placebo administered subcutaneously. The therapies were administered on the same schedule as in the netakimab trial. The primary outcome was also the same.
At week 16, 43.8% of those on the experimental agent versus 24.1% of those randomized to placebo achieved ASAS40 (P = .018). As in the netakimab study, greater activity with brodalumab than placebo was also seen on several secondary outcomes, such as ASAS20 (67.5% vs. 41.8%).
“In a subgroup analysis, there was an advantage for brodalumab over placebo whether or not patients had prior experience with a TNF [tumor necrosis factor] inhibitor, regardless of baseline hs-CRP [high sensitivity C-reactive protein] level and independent of HLA type,” reported James Cheng-Chung Wei, MD, of Chung Shan Medical University Hospital, Taichung, Taiwan.
There were no significant differences in the types or rates of adverse events, including serious adverse events, in patients assigned to brodalumab relative to placebo. Suicide ideation, which has been associated with some biologics targeting other immunologic mediators, was evaluated but not seen.
“We think brodalumab has the potential to be a new therapeutic option in axSpA,” said Dr. Wei, who reported that studies in AS are also planned.
Bimekizumab
Additional 12-week outcome data from the multinational, double-blind, phase 2b BE AGILE trial of bimekizumab in patients with active AS were presented by Désirée van der Heijde, MD, PhD, of Leiden (the Netherlands) University Medical Center.
Unlike secukinumab and most of the other anti–IL-17 receptor monoclonal antibodies in development, bimekizumab inhibits IL-17F in addition to IL-17A, according to Dr. van der Heijde. She cited experimental evidence suggesting that inhibition of both forms of IL-17 results in greater anti-inflammatory response.
In the initial and previously reported data from this dose-ranging study of 303 AS patients, all four doses of bimekizumab (16 mg, 64 mg, 160 mg, or 320 mg) were superior to placebo for the primary endpoint of ASAS40. However, greater relative benefit was observed for the three highest doses.
In the new analysis, symptoms were evaluated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). At 12 weeks, 47.5% of patients on the highest dose of bimekizumab versus only 11.9% of patients randomized to placebo achieved a 50% or greater level of improvement on the BASDAI, called BASDAI 50 (P less than .001).
The greater clinical activity of bimekizumab relative to placebo translated into improvement from baseline in Ankylosing Spondylitis Quality of Life scores. Greater reductions in Ankylosing Spondylitis Quality of Life scores relative to placebo, signaling an improved quality of life, were achieved with all doses, but they reached 4.6 points for the highest dose versus only 1.3 for placebo.
When evaluated with Patient Global Assessment of Disease Activity, another tool that reflects perception of disease burden, the score reduction was 3.3 points for the highest dose versus 1.0 points for placebo. Dr. van der Heijde characterized the reductions at the highest doses versus placebo as “significant” although she did not provide P values.
Like the data presented on the other newer anti–IL-17 therapies, bimekizumab was well tolerated with relatively low rates of adverse events, most of which were mild to moderate in severity, according to Dr. van der Heijde.
“The data from the BE AGILE trial supports phase 3 development in AS,” Dr. van der Heijde said. She noted that trials are also being planned in axSpA.
All three presenting authors reported multiple financial relationships with pharmaceutical companies, including, in each case, the pharmaceutical company that sponsored the trial they presented.
SOURCES: Gaydukova I et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):193-4, Abstract OP0232. doi: 10.1136/annrheumdis-2019-eular.6633; Wei JC et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):195, Abstract OP0234. doi: 10.1136/annrheumdis-2019-eular.6888; van der Heijde D et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):193, Abstract OP0231. doi: 10.1136/annrheumdis-2019-eular.6607.
MADRID – Trial results presented at the European Congress of Rheumatology for three anti–interleukin-17 receptor monoclonal antibodies under investigation for the treatment of axial spondyloarthritis (axSpA), including one for ankylosing spondylitis (AS), appear to support further clinical development and regulatory review to potentially join secukinumab (Cosentyx) and ixekizumab (Taltz) as the only IL-17 inhibitors to be licensed for rheumatic diseases.
Both netakimab and brodalumab (Siliq) achieved positive results in separate phase 3 trials for the treatment of axSpA, while new data from a phase 2b trial of bimekizumab was associated with improvement in the quality of life of patients with AS. Brodalumab is already approved by the Food and Drug Administration for treating moderate to severe plaque psoriasis.
Netakimab
The multinational, double-blind, phase 3 trial with netakimab, called the ASTERA trial, randomized 228 patients with radiographic axSpA to either 120 mg of the experimental agent or placebo, each administered subcutaneously in weekly doses in the first 2 weeks and then every other week thereafter. The primary endpoint was a 40% improvement in Assessment of SpondyloArthritis International Society response criteria (ASAS40) at week 16.
A larger proportion of patients in the netakimab arm met the primary endpoint, compared with those in the placebo arm (40.4% vs. 2.63%, respectively; P less than .0001), reported Inna Gaydukova, MD, of Mechnikov North-Western State Medical University, St. Petersburg, Russia.
“Most of the secondary efficacy endpoints also showed a significant advantage for netakimab relative to placebo by week 4, and these advantages remained significant for the remainder of the study,” she said.
The one serious adverse event in the study occurred in the placebo arm. Although mild to moderate anemia and neutropenia were associated with treatment, the drug was well tolerated overall.
“We did observe a significant reduction in inflammatory activity in the spine with MRI at week 16,” Dr. Gaydukova added. Functional improvements in the experimental arm relative to the placebo arm were also observed, although Dr. Gaydukova acknowledged that longer trials are needed to show that these benefits are durable.
Brodalumab
The results of a multinational, double-blind, phase 3 trial with brodalumab proved similar to those with netakimab. Conducted in Taiwan, Japan, and South Korea, the trial randomized 159 patients to 210 mg of brodalumab or placebo administered subcutaneously. The therapies were administered on the same schedule as in the netakimab trial. The primary outcome was also the same.
At week 16, 43.8% of those on the experimental agent versus 24.1% of those randomized to placebo achieved ASAS40 (P = .018). As in the netakimab study, greater activity with brodalumab than placebo was also seen on several secondary outcomes, such as ASAS20 (67.5% vs. 41.8%).
“In a subgroup analysis, there was an advantage for brodalumab over placebo whether or not patients had prior experience with a TNF [tumor necrosis factor] inhibitor, regardless of baseline hs-CRP [high sensitivity C-reactive protein] level and independent of HLA type,” reported James Cheng-Chung Wei, MD, of Chung Shan Medical University Hospital, Taichung, Taiwan.
There were no significant differences in the types or rates of adverse events, including serious adverse events, in patients assigned to brodalumab relative to placebo. Suicide ideation, which has been associated with some biologics targeting other immunologic mediators, was evaluated but not seen.
“We think brodalumab has the potential to be a new therapeutic option in axSpA,” said Dr. Wei, who reported that studies in AS are also planned.
Bimekizumab
Additional 12-week outcome data from the multinational, double-blind, phase 2b BE AGILE trial of bimekizumab in patients with active AS were presented by Désirée van der Heijde, MD, PhD, of Leiden (the Netherlands) University Medical Center.
Unlike secukinumab and most of the other anti–IL-17 receptor monoclonal antibodies in development, bimekizumab inhibits IL-17F in addition to IL-17A, according to Dr. van der Heijde. She cited experimental evidence suggesting that inhibition of both forms of IL-17 results in greater anti-inflammatory response.
In the initial and previously reported data from this dose-ranging study of 303 AS patients, all four doses of bimekizumab (16 mg, 64 mg, 160 mg, or 320 mg) were superior to placebo for the primary endpoint of ASAS40. However, greater relative benefit was observed for the three highest doses.
In the new analysis, symptoms were evaluated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). At 12 weeks, 47.5% of patients on the highest dose of bimekizumab versus only 11.9% of patients randomized to placebo achieved a 50% or greater level of improvement on the BASDAI, called BASDAI 50 (P less than .001).
The greater clinical activity of bimekizumab relative to placebo translated into improvement from baseline in Ankylosing Spondylitis Quality of Life scores. Greater reductions in Ankylosing Spondylitis Quality of Life scores relative to placebo, signaling an improved quality of life, were achieved with all doses, but they reached 4.6 points for the highest dose versus only 1.3 for placebo.
When evaluated with Patient Global Assessment of Disease Activity, another tool that reflects perception of disease burden, the score reduction was 3.3 points for the highest dose versus 1.0 points for placebo. Dr. van der Heijde characterized the reductions at the highest doses versus placebo as “significant” although she did not provide P values.
Like the data presented on the other newer anti–IL-17 therapies, bimekizumab was well tolerated with relatively low rates of adverse events, most of which were mild to moderate in severity, according to Dr. van der Heijde.
“The data from the BE AGILE trial supports phase 3 development in AS,” Dr. van der Heijde said. She noted that trials are also being planned in axSpA.
All three presenting authors reported multiple financial relationships with pharmaceutical companies, including, in each case, the pharmaceutical company that sponsored the trial they presented.
SOURCES: Gaydukova I et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):193-4, Abstract OP0232. doi: 10.1136/annrheumdis-2019-eular.6633; Wei JC et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):195, Abstract OP0234. doi: 10.1136/annrheumdis-2019-eular.6888; van der Heijde D et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):193, Abstract OP0231. doi: 10.1136/annrheumdis-2019-eular.6607.
REPORTING FROM EULAR 2019 CONGRESS
Secukinumab reduced joint pain of psoriatic arthritis in early data from phase 3b trial
MADRID – Secukinumab was superior to placebo for the primary endpoint of 20% improvement in Assessment of SpondyloArthritis international Society criteria (ASAS20), based on the initial 12-week data from the ongoing phase 3b MAXIMISE trial, the first randomized, controlled trial to evaluate a biologic therapy for the treatment of the axial manifestations of psoriatic arthritis (PsA).
“There was rapid and significant clinical improvement as measured with ASAS20 with both of the study doses of secukinumab,” an anti–interleukin-17 monoclonal antibody, reported Xenofon Baraliakos, MD, of Rheumazentrum Ruhrgebliet, Ruhr-University Bochum in Herne, Germany.
At the European Congress of Rheumatology, Dr. Baraliakos said that the 1-year data will be complete before the end of 2019.
In this primary analysis, 498 patients with established PsA were randomized to 150 mg secukinumab, 300 mg secukinumab, or placebo. For enrollment, all patients were required to have substantial axial pain and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score greater than 4 despite treatment with at least two NSAIDs.
For the first 4 weeks of the trial, patients received their assigned therapies weekly by subcutaneous administration. Treatment thereafter was every 4 weeks.
Almost all patients had active psoriasis and axial symptoms of at least several years duration. The median patient age was 46 years. Approximately one-third were HLA B27 positive.
At baseline, the median back pain score on a visual analog scale of 100 was 73, and the median BASDAI score was greater than 7.0. More than 90% of patients reported back pain worsening with rest.
The proportion of patients achieving ASAS20 at 12 weeks was 63.1% in the group assigned to 300 mg secukinumab, 66.3% in those assigned 150 mg, and 31.1% for those assigned placebo (P less than .0001 for either active therapy versus placebo).
Analyses conducted with multiple imputations and comparing those who were and were not taking methotrexate produced almost the same relative advantage for secukinumab. ASAS20 responses in patients using concomitant methotrexate were 65.1% with 300 mg secukinumab, 67.3% with 150 mg secukinumab, and 33.9% with placebo. Corresponding values in the no-methotrexate group were 60.5%, 64.4%, and 27.1%, respectively.
“There was a good response from either dose of secukinumab no matter what analysis was employed,” reported Dr. Baraliakos, citing an odds ratio of 3.81 for reaching the primary endpoint with secukinumab versus placebo. There were no significant differences in efficacy between the doses of secukinumab.
There was “not much to say about safety,” according to Dr. Baraliakos, as no significant differences in any adverse events were observed between study arms. However, he did caution that longer-term exposure is needed for a more complete analysis of tolerability and safety.
Most patients with PsA are thought to eventually develop axial involvement, which has a major adverse affect on quality of life, according to Dr. Baraliakos. He considers this primary 12-week analysis encouraging, but said the 1-year data will provide more information about whether this therapy should be considered routinely in PsA patients with persistent axial symptoms.
Axial imaging was conducted at study entry even though it was not a criterion for enrollment. Dr. Baraliakos reported that the impact of secukinumab on objective imaging measures of disease activity, if any, is forthcoming.
Imaging data might be needed to establish benefit objectively, judging from a criticism of the study design that arose during discussion after the data were presented. Specifically, it was pointed out that improvement in ASAS20 and BASDAI could occur as a result of improvement in peripheral symptoms, such as enthesitis. The lack of axial-specific outcomes was called a potential weakness of this study.
Dr. Baraliakos countered that BASDAI evaluations did include axial-specific questions, but also confirmed that spine-specific outcomes are included among outcomes to be presented with longer-term analyses.
“These data will come,” said Dr. Baraliakos, referring to imaging as well as other outcomes that will provide more information on the impact of secukinumab in treating the axial involvement of PsA.
Dr. Baraliakos reported multiple financial relationships with pharmaceutical companies, including Novartis, which sponsored this trial.
SOURCE: Ann Rheum Dis. Jun 2019;78(Suppl2):195-6. Abstract OPO235. doi: 10.1136/annrheumdis-2019-eular.2932.
MADRID – Secukinumab was superior to placebo for the primary endpoint of 20% improvement in Assessment of SpondyloArthritis international Society criteria (ASAS20), based on the initial 12-week data from the ongoing phase 3b MAXIMISE trial, the first randomized, controlled trial to evaluate a biologic therapy for the treatment of the axial manifestations of psoriatic arthritis (PsA).
“There was rapid and significant clinical improvement as measured with ASAS20 with both of the study doses of secukinumab,” an anti–interleukin-17 monoclonal antibody, reported Xenofon Baraliakos, MD, of Rheumazentrum Ruhrgebliet, Ruhr-University Bochum in Herne, Germany.
At the European Congress of Rheumatology, Dr. Baraliakos said that the 1-year data will be complete before the end of 2019.
In this primary analysis, 498 patients with established PsA were randomized to 150 mg secukinumab, 300 mg secukinumab, or placebo. For enrollment, all patients were required to have substantial axial pain and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score greater than 4 despite treatment with at least two NSAIDs.
For the first 4 weeks of the trial, patients received their assigned therapies weekly by subcutaneous administration. Treatment thereafter was every 4 weeks.
Almost all patients had active psoriasis and axial symptoms of at least several years duration. The median patient age was 46 years. Approximately one-third were HLA B27 positive.
At baseline, the median back pain score on a visual analog scale of 100 was 73, and the median BASDAI score was greater than 7.0. More than 90% of patients reported back pain worsening with rest.
The proportion of patients achieving ASAS20 at 12 weeks was 63.1% in the group assigned to 300 mg secukinumab, 66.3% in those assigned 150 mg, and 31.1% for those assigned placebo (P less than .0001 for either active therapy versus placebo).
Analyses conducted with multiple imputations and comparing those who were and were not taking methotrexate produced almost the same relative advantage for secukinumab. ASAS20 responses in patients using concomitant methotrexate were 65.1% with 300 mg secukinumab, 67.3% with 150 mg secukinumab, and 33.9% with placebo. Corresponding values in the no-methotrexate group were 60.5%, 64.4%, and 27.1%, respectively.
“There was a good response from either dose of secukinumab no matter what analysis was employed,” reported Dr. Baraliakos, citing an odds ratio of 3.81 for reaching the primary endpoint with secukinumab versus placebo. There were no significant differences in efficacy between the doses of secukinumab.
There was “not much to say about safety,” according to Dr. Baraliakos, as no significant differences in any adverse events were observed between study arms. However, he did caution that longer-term exposure is needed for a more complete analysis of tolerability and safety.
Most patients with PsA are thought to eventually develop axial involvement, which has a major adverse affect on quality of life, according to Dr. Baraliakos. He considers this primary 12-week analysis encouraging, but said the 1-year data will provide more information about whether this therapy should be considered routinely in PsA patients with persistent axial symptoms.
Axial imaging was conducted at study entry even though it was not a criterion for enrollment. Dr. Baraliakos reported that the impact of secukinumab on objective imaging measures of disease activity, if any, is forthcoming.
Imaging data might be needed to establish benefit objectively, judging from a criticism of the study design that arose during discussion after the data were presented. Specifically, it was pointed out that improvement in ASAS20 and BASDAI could occur as a result of improvement in peripheral symptoms, such as enthesitis. The lack of axial-specific outcomes was called a potential weakness of this study.
Dr. Baraliakos countered that BASDAI evaluations did include axial-specific questions, but also confirmed that spine-specific outcomes are included among outcomes to be presented with longer-term analyses.
“These data will come,” said Dr. Baraliakos, referring to imaging as well as other outcomes that will provide more information on the impact of secukinumab in treating the axial involvement of PsA.
Dr. Baraliakos reported multiple financial relationships with pharmaceutical companies, including Novartis, which sponsored this trial.
SOURCE: Ann Rheum Dis. Jun 2019;78(Suppl2):195-6. Abstract OPO235. doi: 10.1136/annrheumdis-2019-eular.2932.
MADRID – Secukinumab was superior to placebo for the primary endpoint of 20% improvement in Assessment of SpondyloArthritis international Society criteria (ASAS20), based on the initial 12-week data from the ongoing phase 3b MAXIMISE trial, the first randomized, controlled trial to evaluate a biologic therapy for the treatment of the axial manifestations of psoriatic arthritis (PsA).
“There was rapid and significant clinical improvement as measured with ASAS20 with both of the study doses of secukinumab,” an anti–interleukin-17 monoclonal antibody, reported Xenofon Baraliakos, MD, of Rheumazentrum Ruhrgebliet, Ruhr-University Bochum in Herne, Germany.
At the European Congress of Rheumatology, Dr. Baraliakos said that the 1-year data will be complete before the end of 2019.
In this primary analysis, 498 patients with established PsA were randomized to 150 mg secukinumab, 300 mg secukinumab, or placebo. For enrollment, all patients were required to have substantial axial pain and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score greater than 4 despite treatment with at least two NSAIDs.
For the first 4 weeks of the trial, patients received their assigned therapies weekly by subcutaneous administration. Treatment thereafter was every 4 weeks.
Almost all patients had active psoriasis and axial symptoms of at least several years duration. The median patient age was 46 years. Approximately one-third were HLA B27 positive.
At baseline, the median back pain score on a visual analog scale of 100 was 73, and the median BASDAI score was greater than 7.0. More than 90% of patients reported back pain worsening with rest.
The proportion of patients achieving ASAS20 at 12 weeks was 63.1% in the group assigned to 300 mg secukinumab, 66.3% in those assigned 150 mg, and 31.1% for those assigned placebo (P less than .0001 for either active therapy versus placebo).
Analyses conducted with multiple imputations and comparing those who were and were not taking methotrexate produced almost the same relative advantage for secukinumab. ASAS20 responses in patients using concomitant methotrexate were 65.1% with 300 mg secukinumab, 67.3% with 150 mg secukinumab, and 33.9% with placebo. Corresponding values in the no-methotrexate group were 60.5%, 64.4%, and 27.1%, respectively.
“There was a good response from either dose of secukinumab no matter what analysis was employed,” reported Dr. Baraliakos, citing an odds ratio of 3.81 for reaching the primary endpoint with secukinumab versus placebo. There were no significant differences in efficacy between the doses of secukinumab.
There was “not much to say about safety,” according to Dr. Baraliakos, as no significant differences in any adverse events were observed between study arms. However, he did caution that longer-term exposure is needed for a more complete analysis of tolerability and safety.
Most patients with PsA are thought to eventually develop axial involvement, which has a major adverse affect on quality of life, according to Dr. Baraliakos. He considers this primary 12-week analysis encouraging, but said the 1-year data will provide more information about whether this therapy should be considered routinely in PsA patients with persistent axial symptoms.
Axial imaging was conducted at study entry even though it was not a criterion for enrollment. Dr. Baraliakos reported that the impact of secukinumab on objective imaging measures of disease activity, if any, is forthcoming.
Imaging data might be needed to establish benefit objectively, judging from a criticism of the study design that arose during discussion after the data were presented. Specifically, it was pointed out that improvement in ASAS20 and BASDAI could occur as a result of improvement in peripheral symptoms, such as enthesitis. The lack of axial-specific outcomes was called a potential weakness of this study.
Dr. Baraliakos countered that BASDAI evaluations did include axial-specific questions, but also confirmed that spine-specific outcomes are included among outcomes to be presented with longer-term analyses.
“These data will come,” said Dr. Baraliakos, referring to imaging as well as other outcomes that will provide more information on the impact of secukinumab in treating the axial involvement of PsA.
Dr. Baraliakos reported multiple financial relationships with pharmaceutical companies, including Novartis, which sponsored this trial.
SOURCE: Ann Rheum Dis. Jun 2019;78(Suppl2):195-6. Abstract OPO235. doi: 10.1136/annrheumdis-2019-eular.2932.
REPORTING FROM EULAR 2019 CONGRESS
Tocilizumab linked to refractory uveitis improvements in some JIA patients
MADRID – Tocilizumab was associated with improved vision in about half of 22 enrolled children with juvenile idiopathic arthritis (JIA) and uveitis refractory to tumor necrosis factor inhibitor (TNFi) therapy, based on results from an investigator-initiated phase 2 trial presented at the European Congress of Rheumatology.
At 12 weeks of treatment, 11 children in the study had some improvement in uveitis and 7 of them had achieved the primary study outcome, which was a two-step decrease in the level of inflammation as measured by the Standard of the Uveitis Nomenclature (SUN) criteria, Athimalaipet V. Ramanan, MBBS, of the department of paediatric rheumatology at the University Hospitals Bristol (England) NHS Foundation Trust, said. Ten of the 21 evaluable patients had no apparent response to tocilizumab. One study participant could not be included in the final analysis because of a violation in study protocol that involved use of disallowed concomitant medications.
“Although this study did not meet the prespecified criterion for efficacy (for most of those treated) ... almost half of those enrolled achieved some benefit,” reported Dr. Ramanan.
The multicenter investigator-initiated phase 2 trial conducted in the United Kingdom enrolled children with JIA and uveitis that was refractory to methotrexate and TNFi therapy. The study participants received methotrexate as well as 162 mg of tocilizumab administered subcutaneously every 2 weeks (those weighing less than 30 kg received tocilizumab treatment every 3 weeks).
Seven of 21 evaluable patients achieved the two-step reduction in inflammation that was the prespecified criterion for a response. For the study population overall, this fell short of statistical significance (P = .11).
However, Dr. Ramanan emphasized that another three patients achieved a one-step improvement, which he believes merits consideration as a sign of efficacy in a “very refractory group.” Moreover, three of four patients with macular edema at baseline had total resolution of this complication.
Other outcomes of interest monitored during the study included the safety and tolerability of tocilizumab and change in use of topical corticosteroids. There were no serious adverse events associated with tocilizumab in this study, according to Dr. Ramanan.
SOURCE: Ann Rheum Dis. Jun 2019;78(Suppl2)265, Abstract LB0011.
MADRID – Tocilizumab was associated with improved vision in about half of 22 enrolled children with juvenile idiopathic arthritis (JIA) and uveitis refractory to tumor necrosis factor inhibitor (TNFi) therapy, based on results from an investigator-initiated phase 2 trial presented at the European Congress of Rheumatology.
At 12 weeks of treatment, 11 children in the study had some improvement in uveitis and 7 of them had achieved the primary study outcome, which was a two-step decrease in the level of inflammation as measured by the Standard of the Uveitis Nomenclature (SUN) criteria, Athimalaipet V. Ramanan, MBBS, of the department of paediatric rheumatology at the University Hospitals Bristol (England) NHS Foundation Trust, said. Ten of the 21 evaluable patients had no apparent response to tocilizumab. One study participant could not be included in the final analysis because of a violation in study protocol that involved use of disallowed concomitant medications.
“Although this study did not meet the prespecified criterion for efficacy (for most of those treated) ... almost half of those enrolled achieved some benefit,” reported Dr. Ramanan.
The multicenter investigator-initiated phase 2 trial conducted in the United Kingdom enrolled children with JIA and uveitis that was refractory to methotrexate and TNFi therapy. The study participants received methotrexate as well as 162 mg of tocilizumab administered subcutaneously every 2 weeks (those weighing less than 30 kg received tocilizumab treatment every 3 weeks).
Seven of 21 evaluable patients achieved the two-step reduction in inflammation that was the prespecified criterion for a response. For the study population overall, this fell short of statistical significance (P = .11).
However, Dr. Ramanan emphasized that another three patients achieved a one-step improvement, which he believes merits consideration as a sign of efficacy in a “very refractory group.” Moreover, three of four patients with macular edema at baseline had total resolution of this complication.
Other outcomes of interest monitored during the study included the safety and tolerability of tocilizumab and change in use of topical corticosteroids. There were no serious adverse events associated with tocilizumab in this study, according to Dr. Ramanan.
SOURCE: Ann Rheum Dis. Jun 2019;78(Suppl2)265, Abstract LB0011.
MADRID – Tocilizumab was associated with improved vision in about half of 22 enrolled children with juvenile idiopathic arthritis (JIA) and uveitis refractory to tumor necrosis factor inhibitor (TNFi) therapy, based on results from an investigator-initiated phase 2 trial presented at the European Congress of Rheumatology.
At 12 weeks of treatment, 11 children in the study had some improvement in uveitis and 7 of them had achieved the primary study outcome, which was a two-step decrease in the level of inflammation as measured by the Standard of the Uveitis Nomenclature (SUN) criteria, Athimalaipet V. Ramanan, MBBS, of the department of paediatric rheumatology at the University Hospitals Bristol (England) NHS Foundation Trust, said. Ten of the 21 evaluable patients had no apparent response to tocilizumab. One study participant could not be included in the final analysis because of a violation in study protocol that involved use of disallowed concomitant medications.
“Although this study did not meet the prespecified criterion for efficacy (for most of those treated) ... almost half of those enrolled achieved some benefit,” reported Dr. Ramanan.
The multicenter investigator-initiated phase 2 trial conducted in the United Kingdom enrolled children with JIA and uveitis that was refractory to methotrexate and TNFi therapy. The study participants received methotrexate as well as 162 mg of tocilizumab administered subcutaneously every 2 weeks (those weighing less than 30 kg received tocilizumab treatment every 3 weeks).
Seven of 21 evaluable patients achieved the two-step reduction in inflammation that was the prespecified criterion for a response. For the study population overall, this fell short of statistical significance (P = .11).
However, Dr. Ramanan emphasized that another three patients achieved a one-step improvement, which he believes merits consideration as a sign of efficacy in a “very refractory group.” Moreover, three of four patients with macular edema at baseline had total resolution of this complication.
Other outcomes of interest monitored during the study included the safety and tolerability of tocilizumab and change in use of topical corticosteroids. There were no serious adverse events associated with tocilizumab in this study, according to Dr. Ramanan.
SOURCE: Ann Rheum Dis. Jun 2019;78(Suppl2)265, Abstract LB0011.
REPORTING FROM EULAR 2019 Congress
Emapalumab produces major responses in macrophage activation syndrome
MADRID – Initial results of an ongoing small pilot study of the anti-interferon gamma (IFN-gamma) monoclonal antibody emapalumab has demonstrated efficacy in the treatment of glucocorticoid-refractory macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (SJIA).
“By week 4 there was a complete response in all six patients treated. All of them had failed conventional therapy,” Fabrizio De Benedetti, MD, PhD, head of the division of rheumatology at IRCCS Ospedale Pediatrico Bambino Gesù, Rome, reported at the European Congress of Rheumatology.
The results are the first of a multicenter, pilot study with twin protocols in Europe and North America. Emapalumab (Gamifant) is already approved by the Food and Drug Administration for the treatment of primary hemophagocytic lymphohistiocytosis (HLH) unresponsive to conventional therapy.
The study is enrolling children with MAS complicating SJIA that is unresponsive to high-dose intravenous glucocorticoids. Emapalumab, which has been shown to neutralize IFN-gamma in animal models, is being administered in an initial dose of 6 mg/kg followed by doses of 3 mg/kg every 3 days for 4 weeks.
MAS is a common complication of rheumatic diseases, particularly SJIA, according to Dr. De Benedetti. It has been characterized as a secondary form of HLH involving an excessive activation and expansion of macrophages as well as T cells. It can produce a wide variety of complications, including hepatosplenomegaly, liver dysfunction, and coagulation abnormalities. If uncontrolled, it can lead to organ failure and death.
Among the first six patients, four had confirmed SJIA and two had presumptive SJIA. The average age was 11 years with a range of 2 to 25 years. Four of the patients were female.
Many of the patients had failed therapies in addition to glucocorticoids, such as cyclosporine and anakinra. A diagnosis of HLH and prior treatment with a biologic therapy were exclusion criteria.
By 8 weeks, six had a complete response, which included the resolution of symptoms by normalization of ferritin, liver enzymes, and D-dimers. In three of the six patients, a complete response was achieved by week 4.
“Steroid tapering by investigator discretion was permitted, and four of the six patients had a meaningful tapering of steroids within 8 weeks,” Dr. De Benedetti reported.
Of the three serious adverse events recorded so far, only reactivation of cytomegalovirus (CMV) infection was attributed to emapalumab. This infection resolved with treatment. Several other infections observed over the course of the study were not thought to be related to treatment.
The initial results have encouraged an expansion of the study protocol in Europe where several treatment centers are expected to begin enrolling patients shortly. A second parallel study protocol will begin soon in North America, but no patient had been treated at the time that Dr. De Benedetti presented these initial findings.
Based on evidence that IFN-gamma drives hyperinflammation and hypercytokinemia in MAS, the initial results with emapalumab are encouraging, according to Dr. De Benedetti. He said the results not only provide evidence that emapalumab is active in MAS but support the pathogenic role of IFN-gamma in this disease.
Dr. De Benedetti reported financial relationships with multiple pharmaceutical companies, including SOBI, the sponsor of this study.
SOURCE: De Benedetti F et al. Ann Rheum Dis. Jun 2019;78(Suppl2):178. Abstract OPO204, doi: 10.1136/annrheumdis-2019-eular.3341.
MADRID – Initial results of an ongoing small pilot study of the anti-interferon gamma (IFN-gamma) monoclonal antibody emapalumab has demonstrated efficacy in the treatment of glucocorticoid-refractory macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (SJIA).
“By week 4 there was a complete response in all six patients treated. All of them had failed conventional therapy,” Fabrizio De Benedetti, MD, PhD, head of the division of rheumatology at IRCCS Ospedale Pediatrico Bambino Gesù, Rome, reported at the European Congress of Rheumatology.
The results are the first of a multicenter, pilot study with twin protocols in Europe and North America. Emapalumab (Gamifant) is already approved by the Food and Drug Administration for the treatment of primary hemophagocytic lymphohistiocytosis (HLH) unresponsive to conventional therapy.
The study is enrolling children with MAS complicating SJIA that is unresponsive to high-dose intravenous glucocorticoids. Emapalumab, which has been shown to neutralize IFN-gamma in animal models, is being administered in an initial dose of 6 mg/kg followed by doses of 3 mg/kg every 3 days for 4 weeks.
MAS is a common complication of rheumatic diseases, particularly SJIA, according to Dr. De Benedetti. It has been characterized as a secondary form of HLH involving an excessive activation and expansion of macrophages as well as T cells. It can produce a wide variety of complications, including hepatosplenomegaly, liver dysfunction, and coagulation abnormalities. If uncontrolled, it can lead to organ failure and death.
Among the first six patients, four had confirmed SJIA and two had presumptive SJIA. The average age was 11 years with a range of 2 to 25 years. Four of the patients were female.
Many of the patients had failed therapies in addition to glucocorticoids, such as cyclosporine and anakinra. A diagnosis of HLH and prior treatment with a biologic therapy were exclusion criteria.
By 8 weeks, six had a complete response, which included the resolution of symptoms by normalization of ferritin, liver enzymes, and D-dimers. In three of the six patients, a complete response was achieved by week 4.
“Steroid tapering by investigator discretion was permitted, and four of the six patients had a meaningful tapering of steroids within 8 weeks,” Dr. De Benedetti reported.
Of the three serious adverse events recorded so far, only reactivation of cytomegalovirus (CMV) infection was attributed to emapalumab. This infection resolved with treatment. Several other infections observed over the course of the study were not thought to be related to treatment.
The initial results have encouraged an expansion of the study protocol in Europe where several treatment centers are expected to begin enrolling patients shortly. A second parallel study protocol will begin soon in North America, but no patient had been treated at the time that Dr. De Benedetti presented these initial findings.
Based on evidence that IFN-gamma drives hyperinflammation and hypercytokinemia in MAS, the initial results with emapalumab are encouraging, according to Dr. De Benedetti. He said the results not only provide evidence that emapalumab is active in MAS but support the pathogenic role of IFN-gamma in this disease.
Dr. De Benedetti reported financial relationships with multiple pharmaceutical companies, including SOBI, the sponsor of this study.
SOURCE: De Benedetti F et al. Ann Rheum Dis. Jun 2019;78(Suppl2):178. Abstract OPO204, doi: 10.1136/annrheumdis-2019-eular.3341.
MADRID – Initial results of an ongoing small pilot study of the anti-interferon gamma (IFN-gamma) monoclonal antibody emapalumab has demonstrated efficacy in the treatment of glucocorticoid-refractory macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (SJIA).
“By week 4 there was a complete response in all six patients treated. All of them had failed conventional therapy,” Fabrizio De Benedetti, MD, PhD, head of the division of rheumatology at IRCCS Ospedale Pediatrico Bambino Gesù, Rome, reported at the European Congress of Rheumatology.
The results are the first of a multicenter, pilot study with twin protocols in Europe and North America. Emapalumab (Gamifant) is already approved by the Food and Drug Administration for the treatment of primary hemophagocytic lymphohistiocytosis (HLH) unresponsive to conventional therapy.
The study is enrolling children with MAS complicating SJIA that is unresponsive to high-dose intravenous glucocorticoids. Emapalumab, which has been shown to neutralize IFN-gamma in animal models, is being administered in an initial dose of 6 mg/kg followed by doses of 3 mg/kg every 3 days for 4 weeks.
MAS is a common complication of rheumatic diseases, particularly SJIA, according to Dr. De Benedetti. It has been characterized as a secondary form of HLH involving an excessive activation and expansion of macrophages as well as T cells. It can produce a wide variety of complications, including hepatosplenomegaly, liver dysfunction, and coagulation abnormalities. If uncontrolled, it can lead to organ failure and death.
Among the first six patients, four had confirmed SJIA and two had presumptive SJIA. The average age was 11 years with a range of 2 to 25 years. Four of the patients were female.
Many of the patients had failed therapies in addition to glucocorticoids, such as cyclosporine and anakinra. A diagnosis of HLH and prior treatment with a biologic therapy were exclusion criteria.
By 8 weeks, six had a complete response, which included the resolution of symptoms by normalization of ferritin, liver enzymes, and D-dimers. In three of the six patients, a complete response was achieved by week 4.
“Steroid tapering by investigator discretion was permitted, and four of the six patients had a meaningful tapering of steroids within 8 weeks,” Dr. De Benedetti reported.
Of the three serious adverse events recorded so far, only reactivation of cytomegalovirus (CMV) infection was attributed to emapalumab. This infection resolved with treatment. Several other infections observed over the course of the study were not thought to be related to treatment.
The initial results have encouraged an expansion of the study protocol in Europe where several treatment centers are expected to begin enrolling patients shortly. A second parallel study protocol will begin soon in North America, but no patient had been treated at the time that Dr. De Benedetti presented these initial findings.
Based on evidence that IFN-gamma drives hyperinflammation and hypercytokinemia in MAS, the initial results with emapalumab are encouraging, according to Dr. De Benedetti. He said the results not only provide evidence that emapalumab is active in MAS but support the pathogenic role of IFN-gamma in this disease.
Dr. De Benedetti reported financial relationships with multiple pharmaceutical companies, including SOBI, the sponsor of this study.
SOURCE: De Benedetti F et al. Ann Rheum Dis. Jun 2019;78(Suppl2):178. Abstract OPO204, doi: 10.1136/annrheumdis-2019-eular.3341.
REPORTING FROM EULAR 2019 CONGRESS