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Book Review: Psychiatrist rejects ‘physician as cog’ model of care
The title of the book, “Passion for Patients,” by Lee H. Beecher, MD, DLFAPA, FASAM, with writer Dave Racer, MLitt (St. Paul, Minn., Alethos Press, 2017), clearly represents Dr. Beecher’s approach to his professional life: His focal interest has been his patients ever since he went to medical school and started a very long and successful practice.
Dr. Beecher’s years of practice encompass many of the changes that the practice of medicine has seen in the last 50 years.
He attended medical school when an office was the place where a physician and his patients would get together to exchange thoughts, feelings, ideas, and plans so that they would eventually work together directly and unencumbered on the same concepts that they share and that they considered crucial to their relationship.
Shortly after Dr. Beecher graduated, Medicaid and Medicare came into medical practice, together with progressive limitations, threats, and a great many unwelcome interlopers, whose mission drastically changed the doctor-patient relationship. No matter how one examines the actions of the numerous new participants – be they auditors, insurance companies, employers, or money managers – one of their main missions was to modify, qualify, re-identify, and limit the interaction between the doctor and the patient.
“What is amazing – and contrary to truth – about the current evolution of medical care reform is its manifold references to safeguarding the best interests of the patient,” Dr. Beecher wrote. “On the contrary, the medical care reformers in current vogue see the physician as but one cog in the production of a specified medical care outcome – a cog that must be greased by evidence-based medicine and managed by analytical applications derived from data, cured in the crucible of number crunching, and controlled by payment systems.”
We live in an age when forces other than medical thinking and practice are trying to define what psychiatrists do, how we do it, and whether our effort is worth being paid for. This has created lack of satisfaction in the exercise of psychiatry, early retirements, and lack of growth in many quarters. When one considers that practically all psychiatric endeavors can be traced to the efforts of devoted practitioners interested in improving the profession, one can see that the future might look bleak because people other than psychiatrists define, quantify, and evaluate the practice of our specialty.
“I escaped from managed care into the practice model that had served so well for decades prior to HMOs, [preferred provider organizations], and other externally controlled practice models,” he wrote. “My patients paid me directly.”
Dr. Beecher is a witness and protester, as well as a thinking innovator, coming to defend patients and physicians at a time when they are under attack from precisely the same forces that were supposed to help and support them.
Throughout his book, Dr. Beecher tells us the story of his many points of disagreement with the intruders and his many arguments in favor of patients and doctors, going back to the beginning of the forces that are controlling and destroying their relationship at this time and advocating principled resistance and a careful search for independence. The reader easily accompanies the author to the points when independence blends with excellence – accepting that neither one exists without the other.
Dr. Muñoz, a former president of the American Psychiatric Association, has written eight books and more than 200 articles about various aspects of psychiatry. He is a professor of psychiatry at the University of California, San Diego, and has a private practice. Dr. Muñoz and Dr. Beecher serve on the Editorial Advisory Board of Clinical Psychiatry News.
The title of the book, “Passion for Patients,” by Lee H. Beecher, MD, DLFAPA, FASAM, with writer Dave Racer, MLitt (St. Paul, Minn., Alethos Press, 2017), clearly represents Dr. Beecher’s approach to his professional life: His focal interest has been his patients ever since he went to medical school and started a very long and successful practice.
Dr. Beecher’s years of practice encompass many of the changes that the practice of medicine has seen in the last 50 years.
He attended medical school when an office was the place where a physician and his patients would get together to exchange thoughts, feelings, ideas, and plans so that they would eventually work together directly and unencumbered on the same concepts that they share and that they considered crucial to their relationship.
Shortly after Dr. Beecher graduated, Medicaid and Medicare came into medical practice, together with progressive limitations, threats, and a great many unwelcome interlopers, whose mission drastically changed the doctor-patient relationship. No matter how one examines the actions of the numerous new participants – be they auditors, insurance companies, employers, or money managers – one of their main missions was to modify, qualify, re-identify, and limit the interaction between the doctor and the patient.
“What is amazing – and contrary to truth – about the current evolution of medical care reform is its manifold references to safeguarding the best interests of the patient,” Dr. Beecher wrote. “On the contrary, the medical care reformers in current vogue see the physician as but one cog in the production of a specified medical care outcome – a cog that must be greased by evidence-based medicine and managed by analytical applications derived from data, cured in the crucible of number crunching, and controlled by payment systems.”
We live in an age when forces other than medical thinking and practice are trying to define what psychiatrists do, how we do it, and whether our effort is worth being paid for. This has created lack of satisfaction in the exercise of psychiatry, early retirements, and lack of growth in many quarters. When one considers that practically all psychiatric endeavors can be traced to the efforts of devoted practitioners interested in improving the profession, one can see that the future might look bleak because people other than psychiatrists define, quantify, and evaluate the practice of our specialty.
“I escaped from managed care into the practice model that had served so well for decades prior to HMOs, [preferred provider organizations], and other externally controlled practice models,” he wrote. “My patients paid me directly.”
Dr. Beecher is a witness and protester, as well as a thinking innovator, coming to defend patients and physicians at a time when they are under attack from precisely the same forces that were supposed to help and support them.
Throughout his book, Dr. Beecher tells us the story of his many points of disagreement with the intruders and his many arguments in favor of patients and doctors, going back to the beginning of the forces that are controlling and destroying their relationship at this time and advocating principled resistance and a careful search for independence. The reader easily accompanies the author to the points when independence blends with excellence – accepting that neither one exists without the other.
Dr. Muñoz, a former president of the American Psychiatric Association, has written eight books and more than 200 articles about various aspects of psychiatry. He is a professor of psychiatry at the University of California, San Diego, and has a private practice. Dr. Muñoz and Dr. Beecher serve on the Editorial Advisory Board of Clinical Psychiatry News.
The title of the book, “Passion for Patients,” by Lee H. Beecher, MD, DLFAPA, FASAM, with writer Dave Racer, MLitt (St. Paul, Minn., Alethos Press, 2017), clearly represents Dr. Beecher’s approach to his professional life: His focal interest has been his patients ever since he went to medical school and started a very long and successful practice.
Dr. Beecher’s years of practice encompass many of the changes that the practice of medicine has seen in the last 50 years.
He attended medical school when an office was the place where a physician and his patients would get together to exchange thoughts, feelings, ideas, and plans so that they would eventually work together directly and unencumbered on the same concepts that they share and that they considered crucial to their relationship.
Shortly after Dr. Beecher graduated, Medicaid and Medicare came into medical practice, together with progressive limitations, threats, and a great many unwelcome interlopers, whose mission drastically changed the doctor-patient relationship. No matter how one examines the actions of the numerous new participants – be they auditors, insurance companies, employers, or money managers – one of their main missions was to modify, qualify, re-identify, and limit the interaction between the doctor and the patient.
“What is amazing – and contrary to truth – about the current evolution of medical care reform is its manifold references to safeguarding the best interests of the patient,” Dr. Beecher wrote. “On the contrary, the medical care reformers in current vogue see the physician as but one cog in the production of a specified medical care outcome – a cog that must be greased by evidence-based medicine and managed by analytical applications derived from data, cured in the crucible of number crunching, and controlled by payment systems.”
We live in an age when forces other than medical thinking and practice are trying to define what psychiatrists do, how we do it, and whether our effort is worth being paid for. This has created lack of satisfaction in the exercise of psychiatry, early retirements, and lack of growth in many quarters. When one considers that practically all psychiatric endeavors can be traced to the efforts of devoted practitioners interested in improving the profession, one can see that the future might look bleak because people other than psychiatrists define, quantify, and evaluate the practice of our specialty.
“I escaped from managed care into the practice model that had served so well for decades prior to HMOs, [preferred provider organizations], and other externally controlled practice models,” he wrote. “My patients paid me directly.”
Dr. Beecher is a witness and protester, as well as a thinking innovator, coming to defend patients and physicians at a time when they are under attack from precisely the same forces that were supposed to help and support them.
Throughout his book, Dr. Beecher tells us the story of his many points of disagreement with the intruders and his many arguments in favor of patients and doctors, going back to the beginning of the forces that are controlling and destroying their relationship at this time and advocating principled resistance and a careful search for independence. The reader easily accompanies the author to the points when independence blends with excellence – accepting that neither one exists without the other.
Dr. Muñoz, a former president of the American Psychiatric Association, has written eight books and more than 200 articles about various aspects of psychiatry. He is a professor of psychiatry at the University of California, San Diego, and has a private practice. Dr. Muñoz and Dr. Beecher serve on the Editorial Advisory Board of Clinical Psychiatry News.
VIDEO: Consider alopecia ‘camouflage kits’ to boost patients’ self-esteem
ORLANDO – The hair loss encounter – which can be challenging for both physicians and patients – should address the negative psychological effects of hair loss, including ways to camouflage hair loss, advised Adriana N. Schmidt, MD, a dermatologist in Santa Monica, Calif.
Dermatologists may spend so much time on the work-up – reviewing history regarding medication, lab values, and hair care practices – that they do not spend time to simply say to patients, “I want to help you feel better about yourself, and here’s how,” she said in a video interview at the annual meeting of the American Academy of Dermatology.
“What we can do is offer them a way to camouflage the hair loss,” Dr. Schmidt said. She shared tips that include creating a kit to keep in the office filled with lists of reputable hairpiece vendors and tattoo specialists in the community, as well as sample wigs, cosmetic powders, and other items to show to patients during hair loss consultations. She also offers thoughts on working with new hair styles and stylists to help improve the self-esteem of alopecia patients.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Schmidt had no relevant disclosures.
[email protected]
On Twitter @whitneymcknight
ORLANDO – The hair loss encounter – which can be challenging for both physicians and patients – should address the negative psychological effects of hair loss, including ways to camouflage hair loss, advised Adriana N. Schmidt, MD, a dermatologist in Santa Monica, Calif.
Dermatologists may spend so much time on the work-up – reviewing history regarding medication, lab values, and hair care practices – that they do not spend time to simply say to patients, “I want to help you feel better about yourself, and here’s how,” she said in a video interview at the annual meeting of the American Academy of Dermatology.
“What we can do is offer them a way to camouflage the hair loss,” Dr. Schmidt said. She shared tips that include creating a kit to keep in the office filled with lists of reputable hairpiece vendors and tattoo specialists in the community, as well as sample wigs, cosmetic powders, and other items to show to patients during hair loss consultations. She also offers thoughts on working with new hair styles and stylists to help improve the self-esteem of alopecia patients.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Schmidt had no relevant disclosures.
[email protected]
On Twitter @whitneymcknight
ORLANDO – The hair loss encounter – which can be challenging for both physicians and patients – should address the negative psychological effects of hair loss, including ways to camouflage hair loss, advised Adriana N. Schmidt, MD, a dermatologist in Santa Monica, Calif.
Dermatologists may spend so much time on the work-up – reviewing history regarding medication, lab values, and hair care practices – that they do not spend time to simply say to patients, “I want to help you feel better about yourself, and here’s how,” she said in a video interview at the annual meeting of the American Academy of Dermatology.
“What we can do is offer them a way to camouflage the hair loss,” Dr. Schmidt said. She shared tips that include creating a kit to keep in the office filled with lists of reputable hairpiece vendors and tattoo specialists in the community, as well as sample wigs, cosmetic powders, and other items to show to patients during hair loss consultations. She also offers thoughts on working with new hair styles and stylists to help improve the self-esteem of alopecia patients.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Schmidt had no relevant disclosures.
[email protected]
On Twitter @whitneymcknight
AT AAD 2017
Improving Caregiver Knowledge of Support Resources
In 2012, 1.3 million veterans who were wounded in action had a severe service-connected disability—nearly triple the number in 2001 (482,000).1 Given the increased number of wounded veterans, the need for caregivers also increased.
The act of caring for an individual with a chronic disability can be a daunting task for the caregiver. However, what is not so commonly recognized is the need for caregiver awareness of the available support resources. Caregivers who do not receive necessary support experience physical and emotional consequences that interfere with their ability to care for veterans with disabilities. Therefore, there is a significant need to provide adequate support for the caregiver to maintain optimum care of the veteran.2
Increased caregiver strain among family caregivers of veterans with long-term disabilities and their lack of knowledge of support resources is a clinical concern. A comprehensive review of the literature provided evidence that access and use of caregiver support resources improved caregiver quality of life.
The purpose of this project was to provide an educational intervention of caregiver resources that were available at the Durham VA Health Care System in North Carolina and in the surrounding community. The desired outcomes included (a) increasing the caregiver’s knowledge of resources available at the VA and within the community to decrease caregiver burden; and (b) assisting the caregiver in determining the best resources for the caregiver and patient. This project was deemed to be a quality improvement project and did not require institutional review board (IRB) approval.
Background
The term strain is used to describe the burden, trouble, or burnout that a caregiver encounters when caring for a person with a long-term illness or disability.3 Caregivers of veterans remain in their role longer and have a heavier burden of care than that of all other caregivers: 65% are in a high-burden caregiving situation compared with 31% nationally.4 The consequence of providing care without assistance has all the features of chronic stress.2 Moreover, the decline of the caregiver’s health can significantly compromise the ability to provide care.3
Empirical observations of the negative health effects of caregiving noted over the past 2 decades have helped convince policymakers that supporting caregivers is an important public health issue.2 To this end, Congress mandated legislation that required the VA to provide a support program for veteran caregivers. In May 2010, President Obama signed the Caregivers and Veterans Omnibus Health Services Act of 2010 into law.1
Supporting Literature
The VA caregiver resource program offers a variety of support resources.1 A better understanding of caregiver needs is necessary to provide the right support resources, improve the health and well-being of caregivers, and make decisions regarding individual caregiving situations.5 For example, respite care offers temporary or periodic relief from caregiving, allowing caregivers to attend to personal tasks, such as shopping, running errands, relaxing, and socializing. This service can increase the physical and mental well-being of the caregiver.6 Studies show that early use of support services is paramount in order for caregivers to receive the greatest positive impact.5
Chen and colleaguesconducted a study of 164 caregivers. The study showed that caregivers who received assistance with accessing the correct support resource exhibited considerably higher satisfaction with the services they received.7 Determining which support therapy was best for the caregiver and the patient for whom they were caring was seen as the initial step. Providing a tool that supplies all the information caregivers need as well as assisting them with accessing services more efficiently is beneficial.
The National Alliance for Caregiving conducted a study to evaluate the needs of caregivers of veterans of various conflicts.4 In the study, caregivers reported that a resource guide would be beneficial. Some of the services they wanted to include in the directory were VA disability benefits, respite care, home health care, hospice services, assisted living, rehabilitation therapies, caregiver support group information, and community resources.
Based on the literature, the author believed that better knowledge of support resources was needed for caregivers. The literature included detailed descriptions of how knowledge of support resources improved caregiver’s well-being by increasing his or her ability to cope with stress related to providing care. However, the literature could have provided a more elaborate discussion on this topic. That was the only weakness identified in each of the studies. Nonetheless, it was clearly noted that resource knowledge yielded a positive effect.
Methods
The project took place at the Durham VA Health Care System and was implemented from August 2015 to October 2015. The participants targeted were caregivers of veterans with disabilities who were considered the veteran’s primary caregiver. Participation was voluntary.
During the veteran’s clinic appointment, the caregiver was given an implied consent letter, pre- and postquestionnaire forms, and a caregiver resource manual. The manual included information on caregiver support resources at the Durham VA Health Care System and in the community (eg, adult day care centers; home-based primary care, hospice care, skilled care, and telehealth; homemaker and home health aide programs; respite care). Other information was provided, such as the Caregiver Support Program application process, contact names, numbers, and helpful websites. Before reading the manual, participants completed the prequestionnaire form and returned it the day of the veteran’s visit. After reading the manual, the caregiver was instructed to complete the postquestionnaire form.
The project coordinator (PC) collaborated with the Veteran Health Education coordinator in developing the caregiver resource manual and questionnaires to ensure that the material met the requirements set forth by the educational program within the Durham VA Health Care System. The PC also collaborated with the Caregiver Support Program subject experts, the chief and acting assistant chief of social work when formulating the contents of the manual and questionnaires. The questionnaires were used to assess the effectiveness of the manual.
The 3 questions on the prequestionnaire and 3 questions on the postquestionnaire were geared to measure the caregiver’s knowledge. There also were 4 questions on the postquestionnaire that were used to address manual revisions.
On the prequestionnaire form, the following questions were asked: (1) If you needed to find caregiver support resources, how much knowledge do you have finding the resources that fit your needs as well as the veteran’s needs? (2) Rate how aware you are with knowing what caregiver support resources are available at the VA and within the community; and (3) Would knowing which caregiver support resources to choose from at the VA and within the community decrease your stress level and give you “peace of mind?”
The same questions were asked postintervention, and the participants were asked to rate their knowledge after reviewing the manual. The participant’s responses on the questionnaires were measured using a 5-point Likert scale.
Participant Demographics
Demographic information was obtained from the cover letter distributed to each participant. The demographic information included age, gender, relationship to the veteran, and number of years to date in the current caregiving role. Participants eligible for inclusion in this project were primary caregivers of veterans with disabilities from all eras of conflict, aged ≥ 18 years.
Fifteen caregivers participated by returning the cover letter containing the implied consent, reading the manual, and completing the pre- and postquestionnaires. There was a wide age range of caregivers who participated, from 29 to 77 years. Of those who responded, there also was a wide range in time in their current caregiving role, ranging from 1 to 41 years. The mean number of years in the current caregiving role was 7 years.
Of the 15 participants, most were female spouses. There were no husbands who participated. The relative’s category included a cousin, a son, and a daughter. The “other” category included a son-in-law and a fiancé.
Data Analysis
Both outcomes were measured using the responses from questions 1 through 3 with the use of running a descriptive statistical analysis. In addition, a t test was used to determine statistical significance, set at α level < .05 of knowledge increase from pre- to postintervention data. Based on the facility, educational benchmarks were set at 80% with the 80% equal to 4 on the Likert scale. Therefore, 80% was the identified benchmark for this project. The goal was that > 70% of the participants would score 80% or better on the postquestionnaire.
Results
Both outcomes were met: (1) increasing the caregiver’s knowledge regarding resources available at the VA and within the community to decrease caregiver burden; and (2) assisting the caregiver in deciding which caregiver resources located in the manual were the right fit for the caregiver and the veteran for whom they were caring. The percentage of participants who scored 80% or better on the prequestionnaire was 54% (n = 8). The postquestionnaire outcomes were considered an improvement based on caregiver’s knowledge of support resources as well as whether the information in the manual decreased their stress level and gave them peace of mind. The intended outcome for the postquestionnaire was that > 70% of the participants would score ≥ 80% after the intervention. This goal was met as final results revealed 73% (n = 11) of the participants scored > 80% on the postquestionnaire.
The postresults supported that caregivers’ knowledge increased, they had peace of mind, and stress levels were decreased with the use of an educational intervention, a comprehensive Caregiver Resource Manual. The postquestionnaire revealed that all of the participants found the Caregiver Resource Manual easy to navigate, and 93% of participants found the Caregiver Resource Manual useful. Out of 15 participants, 8 provided comments. Seven provided positive comments, reporting that the information in the manual was interesting, the manual was simple/easy to read, and the outside resources listed were helpful.
The participant who provided a negative comment was one of the caregivers who did not meet the benchmark of 80% on the pre- or postquestionnaire. The participant was a 33-year-old wife of a veteran with disabilities who had been in the current caregiving role for 9 years. This participant reported that the Caregiver Resource Manual was not geared to younger caregivers, so she would not benefit from using the manual. This caregiver also was the only participant who reported that the Caregiver Resource Manual neither gave her peace of mind nor decreased her stress level.
Comments or suggestions would have been helpful from the other 8 individuals. Because it was not written in the IRB proposal to contact the participants other than to follow-up with telephone calls regarding unreturned questionnaires, no further contact was made with the participants.
Discussion
The preliminary success of this project suggests that there is a significant need for an educational conduit to ensure sufficient caregiver knowledge. Interprofessional collaborative efforts along with using information systems/technology to deliver the Caregiver Resource Manual electronically are important future consideration for improvement of the overall outcomes for a wide range of caregivers, veterans, and health care providers. Health care policy changes on the organizational level, systems level, and national level could further support caregivers of disabled veterans by enabling easy access to caregiver resources as a mandated practice.
Limitations
Limitations centered on the recruitment process. There were a total of 15 caregivers who participated. Although the participation did not meet the PC’s expectation, the final number of participants was adequate in obtaining data regarding evaluating the impact of this project.
Conclusion
The results of this project provided evidence that the Caregiver Resource Manual was effective. Caregivers gained a sense of knowledge and empowerment regarding available resources within the VA and the community. Providing the caregiver with peace of mind and improving the overall health and well-being of the caregiver and veteran were essential.
Moreover, just as the veterans who fought for freedom were equipped with full body armor to help protect them from the potential negative consequences of combat, caregivers who care for these brave soldiers are now equipped with a resource tool and a “full armor of knowledge” to care for their loved ones…our nation’s heroes…our veterans.
1. VA Health Care. Actions needed to address higher-than-expected demand for the family caregiver program. http://www.gao.gov/assets/670/665928.pdf. Published September 18, 2014. Accessed January 9, 2017.
2. Schulz R, Sherwood PR. Physical and mental health effects of family caregiving. Am J Nurs. 2008;108(suppl 9):23-27.
3. Centers for Disease Control; Kimberly-Clark Corporation. Assuring healthy caregivers, a public health approach to translating research into practice: the RE-AIM framework. https://www.cdc.gov /aging/pdf/caregiving_monograph.pdf. Published 2008. Accessed January 9, 2017.
4. National Alliance for Caregiving. Caregivers of veterans—serving on the home front report of study findings. http://www.caregiving.org/data/2010 _Caregivers_of_Veterans_FULLREPORT_WEB _FINAL.pdf. Published 2010. Accessed January 9, 2017.
5. Whittier S, Coon D, Aaker J. Caregiving support interventions. http://cssr.berkeley.edu/pdfs/famcare_04.pdf. Updated 2001. Accessed January 9, 2017.
6. Alzheimer’s Association. Respite care. http://www .alz.org/care/alzheimers-dementia-caregiver-respite.asp. Updated 2016. Accessed January 9, 2017.
7. Chen YM, Hedrick SC, Young HM. A pilot evaluation of the family caregiver support program. Eval Program Plann. 2010;33(2):113-119.
In 2012, 1.3 million veterans who were wounded in action had a severe service-connected disability—nearly triple the number in 2001 (482,000).1 Given the increased number of wounded veterans, the need for caregivers also increased.
The act of caring for an individual with a chronic disability can be a daunting task for the caregiver. However, what is not so commonly recognized is the need for caregiver awareness of the available support resources. Caregivers who do not receive necessary support experience physical and emotional consequences that interfere with their ability to care for veterans with disabilities. Therefore, there is a significant need to provide adequate support for the caregiver to maintain optimum care of the veteran.2
Increased caregiver strain among family caregivers of veterans with long-term disabilities and their lack of knowledge of support resources is a clinical concern. A comprehensive review of the literature provided evidence that access and use of caregiver support resources improved caregiver quality of life.
The purpose of this project was to provide an educational intervention of caregiver resources that were available at the Durham VA Health Care System in North Carolina and in the surrounding community. The desired outcomes included (a) increasing the caregiver’s knowledge of resources available at the VA and within the community to decrease caregiver burden; and (b) assisting the caregiver in determining the best resources for the caregiver and patient. This project was deemed to be a quality improvement project and did not require institutional review board (IRB) approval.
Background
The term strain is used to describe the burden, trouble, or burnout that a caregiver encounters when caring for a person with a long-term illness or disability.3 Caregivers of veterans remain in their role longer and have a heavier burden of care than that of all other caregivers: 65% are in a high-burden caregiving situation compared with 31% nationally.4 The consequence of providing care without assistance has all the features of chronic stress.2 Moreover, the decline of the caregiver’s health can significantly compromise the ability to provide care.3
Empirical observations of the negative health effects of caregiving noted over the past 2 decades have helped convince policymakers that supporting caregivers is an important public health issue.2 To this end, Congress mandated legislation that required the VA to provide a support program for veteran caregivers. In May 2010, President Obama signed the Caregivers and Veterans Omnibus Health Services Act of 2010 into law.1
Supporting Literature
The VA caregiver resource program offers a variety of support resources.1 A better understanding of caregiver needs is necessary to provide the right support resources, improve the health and well-being of caregivers, and make decisions regarding individual caregiving situations.5 For example, respite care offers temporary or periodic relief from caregiving, allowing caregivers to attend to personal tasks, such as shopping, running errands, relaxing, and socializing. This service can increase the physical and mental well-being of the caregiver.6 Studies show that early use of support services is paramount in order for caregivers to receive the greatest positive impact.5
Chen and colleaguesconducted a study of 164 caregivers. The study showed that caregivers who received assistance with accessing the correct support resource exhibited considerably higher satisfaction with the services they received.7 Determining which support therapy was best for the caregiver and the patient for whom they were caring was seen as the initial step. Providing a tool that supplies all the information caregivers need as well as assisting them with accessing services more efficiently is beneficial.
The National Alliance for Caregiving conducted a study to evaluate the needs of caregivers of veterans of various conflicts.4 In the study, caregivers reported that a resource guide would be beneficial. Some of the services they wanted to include in the directory were VA disability benefits, respite care, home health care, hospice services, assisted living, rehabilitation therapies, caregiver support group information, and community resources.
Based on the literature, the author believed that better knowledge of support resources was needed for caregivers. The literature included detailed descriptions of how knowledge of support resources improved caregiver’s well-being by increasing his or her ability to cope with stress related to providing care. However, the literature could have provided a more elaborate discussion on this topic. That was the only weakness identified in each of the studies. Nonetheless, it was clearly noted that resource knowledge yielded a positive effect.
Methods
The project took place at the Durham VA Health Care System and was implemented from August 2015 to October 2015. The participants targeted were caregivers of veterans with disabilities who were considered the veteran’s primary caregiver. Participation was voluntary.
During the veteran’s clinic appointment, the caregiver was given an implied consent letter, pre- and postquestionnaire forms, and a caregiver resource manual. The manual included information on caregiver support resources at the Durham VA Health Care System and in the community (eg, adult day care centers; home-based primary care, hospice care, skilled care, and telehealth; homemaker and home health aide programs; respite care). Other information was provided, such as the Caregiver Support Program application process, contact names, numbers, and helpful websites. Before reading the manual, participants completed the prequestionnaire form and returned it the day of the veteran’s visit. After reading the manual, the caregiver was instructed to complete the postquestionnaire form.
The project coordinator (PC) collaborated with the Veteran Health Education coordinator in developing the caregiver resource manual and questionnaires to ensure that the material met the requirements set forth by the educational program within the Durham VA Health Care System. The PC also collaborated with the Caregiver Support Program subject experts, the chief and acting assistant chief of social work when formulating the contents of the manual and questionnaires. The questionnaires were used to assess the effectiveness of the manual.
The 3 questions on the prequestionnaire and 3 questions on the postquestionnaire were geared to measure the caregiver’s knowledge. There also were 4 questions on the postquestionnaire that were used to address manual revisions.
On the prequestionnaire form, the following questions were asked: (1) If you needed to find caregiver support resources, how much knowledge do you have finding the resources that fit your needs as well as the veteran’s needs? (2) Rate how aware you are with knowing what caregiver support resources are available at the VA and within the community; and (3) Would knowing which caregiver support resources to choose from at the VA and within the community decrease your stress level and give you “peace of mind?”
The same questions were asked postintervention, and the participants were asked to rate their knowledge after reviewing the manual. The participant’s responses on the questionnaires were measured using a 5-point Likert scale.
Participant Demographics
Demographic information was obtained from the cover letter distributed to each participant. The demographic information included age, gender, relationship to the veteran, and number of years to date in the current caregiving role. Participants eligible for inclusion in this project were primary caregivers of veterans with disabilities from all eras of conflict, aged ≥ 18 years.
Fifteen caregivers participated by returning the cover letter containing the implied consent, reading the manual, and completing the pre- and postquestionnaires. There was a wide age range of caregivers who participated, from 29 to 77 years. Of those who responded, there also was a wide range in time in their current caregiving role, ranging from 1 to 41 years. The mean number of years in the current caregiving role was 7 years.
Of the 15 participants, most were female spouses. There were no husbands who participated. The relative’s category included a cousin, a son, and a daughter. The “other” category included a son-in-law and a fiancé.
Data Analysis
Both outcomes were measured using the responses from questions 1 through 3 with the use of running a descriptive statistical analysis. In addition, a t test was used to determine statistical significance, set at α level < .05 of knowledge increase from pre- to postintervention data. Based on the facility, educational benchmarks were set at 80% with the 80% equal to 4 on the Likert scale. Therefore, 80% was the identified benchmark for this project. The goal was that > 70% of the participants would score 80% or better on the postquestionnaire.
Results
Both outcomes were met: (1) increasing the caregiver’s knowledge regarding resources available at the VA and within the community to decrease caregiver burden; and (2) assisting the caregiver in deciding which caregiver resources located in the manual were the right fit for the caregiver and the veteran for whom they were caring. The percentage of participants who scored 80% or better on the prequestionnaire was 54% (n = 8). The postquestionnaire outcomes were considered an improvement based on caregiver’s knowledge of support resources as well as whether the information in the manual decreased their stress level and gave them peace of mind. The intended outcome for the postquestionnaire was that > 70% of the participants would score ≥ 80% after the intervention. This goal was met as final results revealed 73% (n = 11) of the participants scored > 80% on the postquestionnaire.
The postresults supported that caregivers’ knowledge increased, they had peace of mind, and stress levels were decreased with the use of an educational intervention, a comprehensive Caregiver Resource Manual. The postquestionnaire revealed that all of the participants found the Caregiver Resource Manual easy to navigate, and 93% of participants found the Caregiver Resource Manual useful. Out of 15 participants, 8 provided comments. Seven provided positive comments, reporting that the information in the manual was interesting, the manual was simple/easy to read, and the outside resources listed were helpful.
The participant who provided a negative comment was one of the caregivers who did not meet the benchmark of 80% on the pre- or postquestionnaire. The participant was a 33-year-old wife of a veteran with disabilities who had been in the current caregiving role for 9 years. This participant reported that the Caregiver Resource Manual was not geared to younger caregivers, so she would not benefit from using the manual. This caregiver also was the only participant who reported that the Caregiver Resource Manual neither gave her peace of mind nor decreased her stress level.
Comments or suggestions would have been helpful from the other 8 individuals. Because it was not written in the IRB proposal to contact the participants other than to follow-up with telephone calls regarding unreturned questionnaires, no further contact was made with the participants.
Discussion
The preliminary success of this project suggests that there is a significant need for an educational conduit to ensure sufficient caregiver knowledge. Interprofessional collaborative efforts along with using information systems/technology to deliver the Caregiver Resource Manual electronically are important future consideration for improvement of the overall outcomes for a wide range of caregivers, veterans, and health care providers. Health care policy changes on the organizational level, systems level, and national level could further support caregivers of disabled veterans by enabling easy access to caregiver resources as a mandated practice.
Limitations
Limitations centered on the recruitment process. There were a total of 15 caregivers who participated. Although the participation did not meet the PC’s expectation, the final number of participants was adequate in obtaining data regarding evaluating the impact of this project.
Conclusion
The results of this project provided evidence that the Caregiver Resource Manual was effective. Caregivers gained a sense of knowledge and empowerment regarding available resources within the VA and the community. Providing the caregiver with peace of mind and improving the overall health and well-being of the caregiver and veteran were essential.
Moreover, just as the veterans who fought for freedom were equipped with full body armor to help protect them from the potential negative consequences of combat, caregivers who care for these brave soldiers are now equipped with a resource tool and a “full armor of knowledge” to care for their loved ones…our nation’s heroes…our veterans.
In 2012, 1.3 million veterans who were wounded in action had a severe service-connected disability—nearly triple the number in 2001 (482,000).1 Given the increased number of wounded veterans, the need for caregivers also increased.
The act of caring for an individual with a chronic disability can be a daunting task for the caregiver. However, what is not so commonly recognized is the need for caregiver awareness of the available support resources. Caregivers who do not receive necessary support experience physical and emotional consequences that interfere with their ability to care for veterans with disabilities. Therefore, there is a significant need to provide adequate support for the caregiver to maintain optimum care of the veteran.2
Increased caregiver strain among family caregivers of veterans with long-term disabilities and their lack of knowledge of support resources is a clinical concern. A comprehensive review of the literature provided evidence that access and use of caregiver support resources improved caregiver quality of life.
The purpose of this project was to provide an educational intervention of caregiver resources that were available at the Durham VA Health Care System in North Carolina and in the surrounding community. The desired outcomes included (a) increasing the caregiver’s knowledge of resources available at the VA and within the community to decrease caregiver burden; and (b) assisting the caregiver in determining the best resources for the caregiver and patient. This project was deemed to be a quality improvement project and did not require institutional review board (IRB) approval.
Background
The term strain is used to describe the burden, trouble, or burnout that a caregiver encounters when caring for a person with a long-term illness or disability.3 Caregivers of veterans remain in their role longer and have a heavier burden of care than that of all other caregivers: 65% are in a high-burden caregiving situation compared with 31% nationally.4 The consequence of providing care without assistance has all the features of chronic stress.2 Moreover, the decline of the caregiver’s health can significantly compromise the ability to provide care.3
Empirical observations of the negative health effects of caregiving noted over the past 2 decades have helped convince policymakers that supporting caregivers is an important public health issue.2 To this end, Congress mandated legislation that required the VA to provide a support program for veteran caregivers. In May 2010, President Obama signed the Caregivers and Veterans Omnibus Health Services Act of 2010 into law.1
Supporting Literature
The VA caregiver resource program offers a variety of support resources.1 A better understanding of caregiver needs is necessary to provide the right support resources, improve the health and well-being of caregivers, and make decisions regarding individual caregiving situations.5 For example, respite care offers temporary or periodic relief from caregiving, allowing caregivers to attend to personal tasks, such as shopping, running errands, relaxing, and socializing. This service can increase the physical and mental well-being of the caregiver.6 Studies show that early use of support services is paramount in order for caregivers to receive the greatest positive impact.5
Chen and colleaguesconducted a study of 164 caregivers. The study showed that caregivers who received assistance with accessing the correct support resource exhibited considerably higher satisfaction with the services they received.7 Determining which support therapy was best for the caregiver and the patient for whom they were caring was seen as the initial step. Providing a tool that supplies all the information caregivers need as well as assisting them with accessing services more efficiently is beneficial.
The National Alliance for Caregiving conducted a study to evaluate the needs of caregivers of veterans of various conflicts.4 In the study, caregivers reported that a resource guide would be beneficial. Some of the services they wanted to include in the directory were VA disability benefits, respite care, home health care, hospice services, assisted living, rehabilitation therapies, caregiver support group information, and community resources.
Based on the literature, the author believed that better knowledge of support resources was needed for caregivers. The literature included detailed descriptions of how knowledge of support resources improved caregiver’s well-being by increasing his or her ability to cope with stress related to providing care. However, the literature could have provided a more elaborate discussion on this topic. That was the only weakness identified in each of the studies. Nonetheless, it was clearly noted that resource knowledge yielded a positive effect.
Methods
The project took place at the Durham VA Health Care System and was implemented from August 2015 to October 2015. The participants targeted were caregivers of veterans with disabilities who were considered the veteran’s primary caregiver. Participation was voluntary.
During the veteran’s clinic appointment, the caregiver was given an implied consent letter, pre- and postquestionnaire forms, and a caregiver resource manual. The manual included information on caregiver support resources at the Durham VA Health Care System and in the community (eg, adult day care centers; home-based primary care, hospice care, skilled care, and telehealth; homemaker and home health aide programs; respite care). Other information was provided, such as the Caregiver Support Program application process, contact names, numbers, and helpful websites. Before reading the manual, participants completed the prequestionnaire form and returned it the day of the veteran’s visit. After reading the manual, the caregiver was instructed to complete the postquestionnaire form.
The project coordinator (PC) collaborated with the Veteran Health Education coordinator in developing the caregiver resource manual and questionnaires to ensure that the material met the requirements set forth by the educational program within the Durham VA Health Care System. The PC also collaborated with the Caregiver Support Program subject experts, the chief and acting assistant chief of social work when formulating the contents of the manual and questionnaires. The questionnaires were used to assess the effectiveness of the manual.
The 3 questions on the prequestionnaire and 3 questions on the postquestionnaire were geared to measure the caregiver’s knowledge. There also were 4 questions on the postquestionnaire that were used to address manual revisions.
On the prequestionnaire form, the following questions were asked: (1) If you needed to find caregiver support resources, how much knowledge do you have finding the resources that fit your needs as well as the veteran’s needs? (2) Rate how aware you are with knowing what caregiver support resources are available at the VA and within the community; and (3) Would knowing which caregiver support resources to choose from at the VA and within the community decrease your stress level and give you “peace of mind?”
The same questions were asked postintervention, and the participants were asked to rate their knowledge after reviewing the manual. The participant’s responses on the questionnaires were measured using a 5-point Likert scale.
Participant Demographics
Demographic information was obtained from the cover letter distributed to each participant. The demographic information included age, gender, relationship to the veteran, and number of years to date in the current caregiving role. Participants eligible for inclusion in this project were primary caregivers of veterans with disabilities from all eras of conflict, aged ≥ 18 years.
Fifteen caregivers participated by returning the cover letter containing the implied consent, reading the manual, and completing the pre- and postquestionnaires. There was a wide age range of caregivers who participated, from 29 to 77 years. Of those who responded, there also was a wide range in time in their current caregiving role, ranging from 1 to 41 years. The mean number of years in the current caregiving role was 7 years.
Of the 15 participants, most were female spouses. There were no husbands who participated. The relative’s category included a cousin, a son, and a daughter. The “other” category included a son-in-law and a fiancé.
Data Analysis
Both outcomes were measured using the responses from questions 1 through 3 with the use of running a descriptive statistical analysis. In addition, a t test was used to determine statistical significance, set at α level < .05 of knowledge increase from pre- to postintervention data. Based on the facility, educational benchmarks were set at 80% with the 80% equal to 4 on the Likert scale. Therefore, 80% was the identified benchmark for this project. The goal was that > 70% of the participants would score 80% or better on the postquestionnaire.
Results
Both outcomes were met: (1) increasing the caregiver’s knowledge regarding resources available at the VA and within the community to decrease caregiver burden; and (2) assisting the caregiver in deciding which caregiver resources located in the manual were the right fit for the caregiver and the veteran for whom they were caring. The percentage of participants who scored 80% or better on the prequestionnaire was 54% (n = 8). The postquestionnaire outcomes were considered an improvement based on caregiver’s knowledge of support resources as well as whether the information in the manual decreased their stress level and gave them peace of mind. The intended outcome for the postquestionnaire was that > 70% of the participants would score ≥ 80% after the intervention. This goal was met as final results revealed 73% (n = 11) of the participants scored > 80% on the postquestionnaire.
The postresults supported that caregivers’ knowledge increased, they had peace of mind, and stress levels were decreased with the use of an educational intervention, a comprehensive Caregiver Resource Manual. The postquestionnaire revealed that all of the participants found the Caregiver Resource Manual easy to navigate, and 93% of participants found the Caregiver Resource Manual useful. Out of 15 participants, 8 provided comments. Seven provided positive comments, reporting that the information in the manual was interesting, the manual was simple/easy to read, and the outside resources listed were helpful.
The participant who provided a negative comment was one of the caregivers who did not meet the benchmark of 80% on the pre- or postquestionnaire. The participant was a 33-year-old wife of a veteran with disabilities who had been in the current caregiving role for 9 years. This participant reported that the Caregiver Resource Manual was not geared to younger caregivers, so she would not benefit from using the manual. This caregiver also was the only participant who reported that the Caregiver Resource Manual neither gave her peace of mind nor decreased her stress level.
Comments or suggestions would have been helpful from the other 8 individuals. Because it was not written in the IRB proposal to contact the participants other than to follow-up with telephone calls regarding unreturned questionnaires, no further contact was made with the participants.
Discussion
The preliminary success of this project suggests that there is a significant need for an educational conduit to ensure sufficient caregiver knowledge. Interprofessional collaborative efforts along with using information systems/technology to deliver the Caregiver Resource Manual electronically are important future consideration for improvement of the overall outcomes for a wide range of caregivers, veterans, and health care providers. Health care policy changes on the organizational level, systems level, and national level could further support caregivers of disabled veterans by enabling easy access to caregiver resources as a mandated practice.
Limitations
Limitations centered on the recruitment process. There were a total of 15 caregivers who participated. Although the participation did not meet the PC’s expectation, the final number of participants was adequate in obtaining data regarding evaluating the impact of this project.
Conclusion
The results of this project provided evidence that the Caregiver Resource Manual was effective. Caregivers gained a sense of knowledge and empowerment regarding available resources within the VA and the community. Providing the caregiver with peace of mind and improving the overall health and well-being of the caregiver and veteran were essential.
Moreover, just as the veterans who fought for freedom were equipped with full body armor to help protect them from the potential negative consequences of combat, caregivers who care for these brave soldiers are now equipped with a resource tool and a “full armor of knowledge” to care for their loved ones…our nation’s heroes…our veterans.
1. VA Health Care. Actions needed to address higher-than-expected demand for the family caregiver program. http://www.gao.gov/assets/670/665928.pdf. Published September 18, 2014. Accessed January 9, 2017.
2. Schulz R, Sherwood PR. Physical and mental health effects of family caregiving. Am J Nurs. 2008;108(suppl 9):23-27.
3. Centers for Disease Control; Kimberly-Clark Corporation. Assuring healthy caregivers, a public health approach to translating research into practice: the RE-AIM framework. https://www.cdc.gov /aging/pdf/caregiving_monograph.pdf. Published 2008. Accessed January 9, 2017.
4. National Alliance for Caregiving. Caregivers of veterans—serving on the home front report of study findings. http://www.caregiving.org/data/2010 _Caregivers_of_Veterans_FULLREPORT_WEB _FINAL.pdf. Published 2010. Accessed January 9, 2017.
5. Whittier S, Coon D, Aaker J. Caregiving support interventions. http://cssr.berkeley.edu/pdfs/famcare_04.pdf. Updated 2001. Accessed January 9, 2017.
6. Alzheimer’s Association. Respite care. http://www .alz.org/care/alzheimers-dementia-caregiver-respite.asp. Updated 2016. Accessed January 9, 2017.
7. Chen YM, Hedrick SC, Young HM. A pilot evaluation of the family caregiver support program. Eval Program Plann. 2010;33(2):113-119.
1. VA Health Care. Actions needed to address higher-than-expected demand for the family caregiver program. http://www.gao.gov/assets/670/665928.pdf. Published September 18, 2014. Accessed January 9, 2017.
2. Schulz R, Sherwood PR. Physical and mental health effects of family caregiving. Am J Nurs. 2008;108(suppl 9):23-27.
3. Centers for Disease Control; Kimberly-Clark Corporation. Assuring healthy caregivers, a public health approach to translating research into practice: the RE-AIM framework. https://www.cdc.gov /aging/pdf/caregiving_monograph.pdf. Published 2008. Accessed January 9, 2017.
4. National Alliance for Caregiving. Caregivers of veterans—serving on the home front report of study findings. http://www.caregiving.org/data/2010 _Caregivers_of_Veterans_FULLREPORT_WEB _FINAL.pdf. Published 2010. Accessed January 9, 2017.
5. Whittier S, Coon D, Aaker J. Caregiving support interventions. http://cssr.berkeley.edu/pdfs/famcare_04.pdf. Updated 2001. Accessed January 9, 2017.
6. Alzheimer’s Association. Respite care. http://www .alz.org/care/alzheimers-dementia-caregiver-respite.asp. Updated 2016. Accessed January 9, 2017.
7. Chen YM, Hedrick SC, Young HM. A pilot evaluation of the family caregiver support program. Eval Program Plann. 2010;33(2):113-119.
Oxybutynin Treatment for Hyperhidrosis in Spinal Cord Injury Patients
Hyperhidrosis (HH) is sweating beyond that which is required for thermoregulation.1 Secondary HH, which is usually caused by an underlying medical condition or drug, may be seen in patients with spinal cord injury (SCI) and can negatively impact psychosocial well-being and quality of life (QOL) if not treated.1
Information on the current prevalence of HH is lacking. In 2004, one study projected the prevalence of HH in the U.S. to be 2.8%.2 A previous study found that about 27% of the 154 patients with SCI reported experiencing HH that was annoying, with 28 (14.6%) of those reporting no contributing somatic causes.3 Somatic causes of HH include autonomic dysreflexia, posttraumatic syringomyelia, or orthostatic hypotension.4
Autonomic dysreflexia is a syndrome that describes a dramatic increase in blood pressure (BP) in patients with spinal cord lesion at or above T6 and is characterized by exaggerated autonomic responses to stimuli that are innocuous to individuals without SCI.5,6 Noxious stimuli that may trigger autonomic dysreflexia include bowel or bladder distension or obstruction, urinary infection, catheter insertion, suprapubic palpation, or skin irritation.6 Syringomyelia, another somatic cause of HH, is a cystic lesion on the spinal cord that may develop secondary to congenital anomalies or SCI.6-8
The following case reports describe 2 patients with SCI with different diagnoses and presentations of HH. Both were treated with oxybutynin for HH.
Case 1 Presentation
Mr. J is a 49-year-old with C6-C7 SCI attributed to a motor vehicle accident 26 years before. He presented to the primary care clinic for a routine visit in a self-propelled wheelchair. His diagnosis included tetraplegia, muscle spasms, osteoporosis, chronic pain syndrome, benign prosthetic hypertrophy, neurogenic bladder, and neurogenic bowel. He was noted to have a bath towel around his neck to wipe sweat from his face and neck. He did not recall when this condition started; however, he reported a prior trial of diazepam 5 mg as needed in 2006 in the mornings and before transfers when sweating was usually worst. He continued to use diazepam because it helped with his muscle spasms but not with sweating. His other medications included oral baclofen, alendronate, ibuprofen, docusate sodium, tamsulosin, calcium/vitamin C supplement, and bisacodyl suppository.
The patient’s surgical history was significant for anterior discectomy with C6-C7 fusion, sphincterotomy, transurethral resection of the prostate, and right urethral stent placement for hydronephrosis in 2004. His cystoscopy and renal sonogram were within normal limits. On physical examination, his vital signs were within normal limits. However, his long-sleeved shirt was wet on the front, and his neck, chest, and arms also were moist from excessive sweating. During his transfer to and from his wheelchair, he was noted to have chattering of his teeth. The remainder of the physical examination was negative for any other acute findings.
Mr. J was prescribed a 30-day trial of oxybutynin 5 mg 1 tablet by mouth per day for HH. During a 3-week follow-up telephone call, Mr. J reported that the oxybutynin was working well; the sweating on his chest had improved and had resolved on his face. Except for mild dryness of mouth, he was tolerating the medication well. There were no changes in his neurogenic bladder, which was managed with an external urinary device.
Six months later, Mr. J reported that oxybutynin continued to work well, and he no longer had to travel with a towel. He was able to go to a football game, social activities were more enjoyable, and he was not embarrassed because of excessive sweating.
Case 2 Presentation
Mr. B is a 48-year-old with T12 paraplegia secondary to a motor vehicle accident in 1994. He called the primary clinic for a visit because he was concerned about cold clammy hands for the past 6 to 7 months when he woke up in the morning and sometimes throughout the day. He was preparing to start his first semester in college. His diagnosis included neurogenic bowel and bladder and muscle spasms. There was no history of posttraumatic syringomyelia, and his medications included baclofen, dantrolene, diazepam, and multivitamins.
Mr. B took tolterodine 4 mg/d for several years, and for unknown reasons, about 6 years previously the prescription was changed to oxybutynin 15-mg extended release for his neurogenic bladder. He continued to have urinary leakage between the every 4-hour intermittent catherization, and oxybutynin was increased to 10-mg tablet twice per day.
About 7 months prior to this appointment, Mr. B independently stopped the oxybutynin as he felt that it was not making a difference in the management of his neurogenic bladder. It was noted that his cold clammy hands started about the same time that he discontinued the oxybutynin. He could not recall whether he had this symptom prior to initiation of any medication. It was mutually decided to restart the oxybutynin at a lower dose, this time not for his bladder but for the HH. He was ordered a 30-day trial of a 5-mg tablet once per day. About 3 weeks later, he sent a secure message to report oxybutynin’s effectiveness and to request a refill.
Discussion
Sweating is a physiological process that involves the active secretion of water by specialized sweat glands in the skin.9-11 There are 2 types of sweat glands in the skin; apocrine and eccrine.9 Collectively the 3 million eccrine sweat glands of the average person approximately equal the mass of a kidney and exceed the secretory rate of exocrine glands.9 They function in evaporative cooling in response to thermal or physiologic stimuli and are widely distributed over the body, especially on the forehead, back, palms, and soles.10
Sympathetic cholinergic nerves are mainly responsible for sweat secretion by the release of acetylcholine to activate muscarinic receptors on the gland.11 Postganglionic fibers from sympathetic nerve cells innervate sweat glands that release cholinergics.6 Postganglionic cholinergic receptors that are activated by muscarinic drugs are termed muscarinic receptors and are readily accessible to antimuscarinic drugs.6,12 Anticholinergic/antimuscarinic agents antagonize muscarinic receptors and suppress premature detrusor contractions to enhance bladder storage.13 They include oxybutynin, tolterodine, trospium, solifenacin, darifenacin, and fesoterodine.13 Oxybutynin was used in both cases because it is on VA formulary. It was effective in treating HH, although the etiology is unclear and the presentations were different.
One retrospective study that analyzed 20 patients who received oxybutynin for primary HH at uncommon sites, such as the back and groin, found that QOL improved in 85% of the subjects after 6 weeks.14 Randomized placebo-controlled trials also have found oxybutynin effective for treatment of palmar and axillary HH and generalized HH.15,16
Syringomyelia was ruled out in both cases based on history and radiologic studies, specifically magnetic resonance imaging. Autonomic dysreflexia was ruled out as the HH was not an acute finding and BP was within normal limits. Orthostatic hypotension is a common finding in SCI, mainly in tetraplegic patients, and could be suspected in both cases. Sweating was usually worse in the mornings in both cases and during transfers, as noted in the first case.17 However, chronic autoregulation allows for chronic adaption to tissue hypoperfusion over time.16
Hyperhidrosis or other disorders of eccrine sweating can occur for various reasons, including changes in the spinal sympathetic preganglionic, ganglionic, or postganglionic neurons; dysfunction of the thermoregulatory centers in the brain’s central autonomic network; or changes in the muscarinic cholinergic synapse on sweat glands.18
Conclusion
Patients with SCI may have an acute or chronic presentation of HH. Removal of the inciting cause in the case of autonomic dysreflexia and/or the administration of a pharmaceutical agent is the usual treatment.
Regardless of the etiology of HH that persists, effective treatment should be a goal, especially in those patients whose QOL is affected by this condition. The outcome of treatment with oxybutynin in these case reports is consistent with the findings of the limited retrospective study and randomized placebo-controlled studies that show oxybutynin is effective for treating bothersome HH.14-16
The results of these case reports are not generalizable to patients with SCI and HH, nor are the results of the limited retrospective study and randomized placebo-controlled studies, as their sample sizes were small.14,16,17 However, information on the use of oxybutynin for the effective treatment of HH in the SCI population is promising. Research studies on the prevalence of HH and randomized placebo-controlled trials with a larger SCI population are considerations for future studies.
1. Strutton DR, Kowalski JW, Glaser DA, Stang PE. US prevalence of hyperhidrosis and impact on individuals with axillary hyperhidrosis: results from a national survey. J Am Acad Dermatol. 2004;51(2):241-248.
2. Walling HW. Clinical differentiation of primary from secondary hyperhidrosis. J Am Acad Dermatol. 2011;64(4):690-695.
3. Andersen LS, Biering-Sørensen F, Müller PG, Jensen IL, Aggerbeck B. The prevalence of hyperhidrosis in patients with spinal cord injuries and an evaluation of the effect of dextropropoxyphene hydrochloride in therapy. Paraplegia. 1992;(30):184-191.
4. Sato K, Kang WH, Saga K, Sato KT. Biology of sweat glands and their disorders. II. Disorders of sweat gland function. J Am Acad Dermatol. 1989;20(5, pt 1):713-726.
5. Kewalramani LS. Autonomic dysreflexia in traumatic myelopathy. Am J Phys Med. 1980;59(1):1-21.
6. Low PA, Engstrom JW. Disorders of the autonomic nervous system. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015.
7. Milhort TH. Classification of syringomyelia. Neurosurg Focus. 2000;8(3):E1.
8. National Institute of Neurological Disorders and Stroke. Syringomyelia fact sheet. https://www.ninds .nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Syringomyelia-Fact-Sheet. Accessed February 13, 2017.
9. Meschner AL. Junqueira’s Basic Histology. 14th ed. New York, NY: McGraw-Hill; 2016:371-392.
10. Mauro TM. Biology of eccrine and apocrine glands. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012.
11. Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical Physiology. 25th ed. New York, NY: McGraw-Hill; 2016:261-272.
12. Kellogg DL Jr. Thermoregulation. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012.
13. Rovner ES, Wyman J, Lam S. Urinary Incontinence. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill; 2014:1377-1396.
14. Teivelis MP, Wolosker N, Krutman M, Kauffman P, Campos JR, Puech-Leão P. Treatment of uncommon sites of focal primary hyperhidrosis: experience with pharmacological therapy using oxybutynin. Clinics (Sao Paulo). 2014;69(9):608-614.
15. Wolosker N, de Campos JR, Kauffman P, Puech-Leão P. A randomized-placebo-controlled trial of oxybutynin for the initial treatment of palmar and axillary hyperhidrosis. J Vasc Surg. 2012;55(6):1696-1700.
16. Schollhammer M, Brenaut E, Menard-Andivot N, et al. Oxybutynin as a treatment for generalized hyperhidrosis. Br J Dermatol. 2015;173(5):1163-1168.
17. Gonzalez F, Chang JY, Banovac K, Messina D, Martinez-Arizala A, Kelley RE. Autoregulation of cerebral blood flow in patients with orthostatic hypotension after spinal cord injury. Paraplegia. 1991;29(1):1-7.
18. Fealey RD, Hebert AA. Disorders of the eccrine sweat glands and sweating. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick’s Dermatology in General Medicine. New York, NY: McGraw-Hill; 2012:chap 84.
Hyperhidrosis (HH) is sweating beyond that which is required for thermoregulation.1 Secondary HH, which is usually caused by an underlying medical condition or drug, may be seen in patients with spinal cord injury (SCI) and can negatively impact psychosocial well-being and quality of life (QOL) if not treated.1
Information on the current prevalence of HH is lacking. In 2004, one study projected the prevalence of HH in the U.S. to be 2.8%.2 A previous study found that about 27% of the 154 patients with SCI reported experiencing HH that was annoying, with 28 (14.6%) of those reporting no contributing somatic causes.3 Somatic causes of HH include autonomic dysreflexia, posttraumatic syringomyelia, or orthostatic hypotension.4
Autonomic dysreflexia is a syndrome that describes a dramatic increase in blood pressure (BP) in patients with spinal cord lesion at or above T6 and is characterized by exaggerated autonomic responses to stimuli that are innocuous to individuals without SCI.5,6 Noxious stimuli that may trigger autonomic dysreflexia include bowel or bladder distension or obstruction, urinary infection, catheter insertion, suprapubic palpation, or skin irritation.6 Syringomyelia, another somatic cause of HH, is a cystic lesion on the spinal cord that may develop secondary to congenital anomalies or SCI.6-8
The following case reports describe 2 patients with SCI with different diagnoses and presentations of HH. Both were treated with oxybutynin for HH.
Case 1 Presentation
Mr. J is a 49-year-old with C6-C7 SCI attributed to a motor vehicle accident 26 years before. He presented to the primary care clinic for a routine visit in a self-propelled wheelchair. His diagnosis included tetraplegia, muscle spasms, osteoporosis, chronic pain syndrome, benign prosthetic hypertrophy, neurogenic bladder, and neurogenic bowel. He was noted to have a bath towel around his neck to wipe sweat from his face and neck. He did not recall when this condition started; however, he reported a prior trial of diazepam 5 mg as needed in 2006 in the mornings and before transfers when sweating was usually worst. He continued to use diazepam because it helped with his muscle spasms but not with sweating. His other medications included oral baclofen, alendronate, ibuprofen, docusate sodium, tamsulosin, calcium/vitamin C supplement, and bisacodyl suppository.
The patient’s surgical history was significant for anterior discectomy with C6-C7 fusion, sphincterotomy, transurethral resection of the prostate, and right urethral stent placement for hydronephrosis in 2004. His cystoscopy and renal sonogram were within normal limits. On physical examination, his vital signs were within normal limits. However, his long-sleeved shirt was wet on the front, and his neck, chest, and arms also were moist from excessive sweating. During his transfer to and from his wheelchair, he was noted to have chattering of his teeth. The remainder of the physical examination was negative for any other acute findings.
Mr. J was prescribed a 30-day trial of oxybutynin 5 mg 1 tablet by mouth per day for HH. During a 3-week follow-up telephone call, Mr. J reported that the oxybutynin was working well; the sweating on his chest had improved and had resolved on his face. Except for mild dryness of mouth, he was tolerating the medication well. There were no changes in his neurogenic bladder, which was managed with an external urinary device.
Six months later, Mr. J reported that oxybutynin continued to work well, and he no longer had to travel with a towel. He was able to go to a football game, social activities were more enjoyable, and he was not embarrassed because of excessive sweating.
Case 2 Presentation
Mr. B is a 48-year-old with T12 paraplegia secondary to a motor vehicle accident in 1994. He called the primary clinic for a visit because he was concerned about cold clammy hands for the past 6 to 7 months when he woke up in the morning and sometimes throughout the day. He was preparing to start his first semester in college. His diagnosis included neurogenic bowel and bladder and muscle spasms. There was no history of posttraumatic syringomyelia, and his medications included baclofen, dantrolene, diazepam, and multivitamins.
Mr. B took tolterodine 4 mg/d for several years, and for unknown reasons, about 6 years previously the prescription was changed to oxybutynin 15-mg extended release for his neurogenic bladder. He continued to have urinary leakage between the every 4-hour intermittent catherization, and oxybutynin was increased to 10-mg tablet twice per day.
About 7 months prior to this appointment, Mr. B independently stopped the oxybutynin as he felt that it was not making a difference in the management of his neurogenic bladder. It was noted that his cold clammy hands started about the same time that he discontinued the oxybutynin. He could not recall whether he had this symptom prior to initiation of any medication. It was mutually decided to restart the oxybutynin at a lower dose, this time not for his bladder but for the HH. He was ordered a 30-day trial of a 5-mg tablet once per day. About 3 weeks later, he sent a secure message to report oxybutynin’s effectiveness and to request a refill.
Discussion
Sweating is a physiological process that involves the active secretion of water by specialized sweat glands in the skin.9-11 There are 2 types of sweat glands in the skin; apocrine and eccrine.9 Collectively the 3 million eccrine sweat glands of the average person approximately equal the mass of a kidney and exceed the secretory rate of exocrine glands.9 They function in evaporative cooling in response to thermal or physiologic stimuli and are widely distributed over the body, especially on the forehead, back, palms, and soles.10
Sympathetic cholinergic nerves are mainly responsible for sweat secretion by the release of acetylcholine to activate muscarinic receptors on the gland.11 Postganglionic fibers from sympathetic nerve cells innervate sweat glands that release cholinergics.6 Postganglionic cholinergic receptors that are activated by muscarinic drugs are termed muscarinic receptors and are readily accessible to antimuscarinic drugs.6,12 Anticholinergic/antimuscarinic agents antagonize muscarinic receptors and suppress premature detrusor contractions to enhance bladder storage.13 They include oxybutynin, tolterodine, trospium, solifenacin, darifenacin, and fesoterodine.13 Oxybutynin was used in both cases because it is on VA formulary. It was effective in treating HH, although the etiology is unclear and the presentations were different.
One retrospective study that analyzed 20 patients who received oxybutynin for primary HH at uncommon sites, such as the back and groin, found that QOL improved in 85% of the subjects after 6 weeks.14 Randomized placebo-controlled trials also have found oxybutynin effective for treatment of palmar and axillary HH and generalized HH.15,16
Syringomyelia was ruled out in both cases based on history and radiologic studies, specifically magnetic resonance imaging. Autonomic dysreflexia was ruled out as the HH was not an acute finding and BP was within normal limits. Orthostatic hypotension is a common finding in SCI, mainly in tetraplegic patients, and could be suspected in both cases. Sweating was usually worse in the mornings in both cases and during transfers, as noted in the first case.17 However, chronic autoregulation allows for chronic adaption to tissue hypoperfusion over time.16
Hyperhidrosis or other disorders of eccrine sweating can occur for various reasons, including changes in the spinal sympathetic preganglionic, ganglionic, or postganglionic neurons; dysfunction of the thermoregulatory centers in the brain’s central autonomic network; or changes in the muscarinic cholinergic synapse on sweat glands.18
Conclusion
Patients with SCI may have an acute or chronic presentation of HH. Removal of the inciting cause in the case of autonomic dysreflexia and/or the administration of a pharmaceutical agent is the usual treatment.
Regardless of the etiology of HH that persists, effective treatment should be a goal, especially in those patients whose QOL is affected by this condition. The outcome of treatment with oxybutynin in these case reports is consistent with the findings of the limited retrospective study and randomized placebo-controlled studies that show oxybutynin is effective for treating bothersome HH.14-16
The results of these case reports are not generalizable to patients with SCI and HH, nor are the results of the limited retrospective study and randomized placebo-controlled studies, as their sample sizes were small.14,16,17 However, information on the use of oxybutynin for the effective treatment of HH in the SCI population is promising. Research studies on the prevalence of HH and randomized placebo-controlled trials with a larger SCI population are considerations for future studies.
Hyperhidrosis (HH) is sweating beyond that which is required for thermoregulation.1 Secondary HH, which is usually caused by an underlying medical condition or drug, may be seen in patients with spinal cord injury (SCI) and can negatively impact psychosocial well-being and quality of life (QOL) if not treated.1
Information on the current prevalence of HH is lacking. In 2004, one study projected the prevalence of HH in the U.S. to be 2.8%.2 A previous study found that about 27% of the 154 patients with SCI reported experiencing HH that was annoying, with 28 (14.6%) of those reporting no contributing somatic causes.3 Somatic causes of HH include autonomic dysreflexia, posttraumatic syringomyelia, or orthostatic hypotension.4
Autonomic dysreflexia is a syndrome that describes a dramatic increase in blood pressure (BP) in patients with spinal cord lesion at or above T6 and is characterized by exaggerated autonomic responses to stimuli that are innocuous to individuals without SCI.5,6 Noxious stimuli that may trigger autonomic dysreflexia include bowel or bladder distension or obstruction, urinary infection, catheter insertion, suprapubic palpation, or skin irritation.6 Syringomyelia, another somatic cause of HH, is a cystic lesion on the spinal cord that may develop secondary to congenital anomalies or SCI.6-8
The following case reports describe 2 patients with SCI with different diagnoses and presentations of HH. Both were treated with oxybutynin for HH.
Case 1 Presentation
Mr. J is a 49-year-old with C6-C7 SCI attributed to a motor vehicle accident 26 years before. He presented to the primary care clinic for a routine visit in a self-propelled wheelchair. His diagnosis included tetraplegia, muscle spasms, osteoporosis, chronic pain syndrome, benign prosthetic hypertrophy, neurogenic bladder, and neurogenic bowel. He was noted to have a bath towel around his neck to wipe sweat from his face and neck. He did not recall when this condition started; however, he reported a prior trial of diazepam 5 mg as needed in 2006 in the mornings and before transfers when sweating was usually worst. He continued to use diazepam because it helped with his muscle spasms but not with sweating. His other medications included oral baclofen, alendronate, ibuprofen, docusate sodium, tamsulosin, calcium/vitamin C supplement, and bisacodyl suppository.
The patient’s surgical history was significant for anterior discectomy with C6-C7 fusion, sphincterotomy, transurethral resection of the prostate, and right urethral stent placement for hydronephrosis in 2004. His cystoscopy and renal sonogram were within normal limits. On physical examination, his vital signs were within normal limits. However, his long-sleeved shirt was wet on the front, and his neck, chest, and arms also were moist from excessive sweating. During his transfer to and from his wheelchair, he was noted to have chattering of his teeth. The remainder of the physical examination was negative for any other acute findings.
Mr. J was prescribed a 30-day trial of oxybutynin 5 mg 1 tablet by mouth per day for HH. During a 3-week follow-up telephone call, Mr. J reported that the oxybutynin was working well; the sweating on his chest had improved and had resolved on his face. Except for mild dryness of mouth, he was tolerating the medication well. There were no changes in his neurogenic bladder, which was managed with an external urinary device.
Six months later, Mr. J reported that oxybutynin continued to work well, and he no longer had to travel with a towel. He was able to go to a football game, social activities were more enjoyable, and he was not embarrassed because of excessive sweating.
Case 2 Presentation
Mr. B is a 48-year-old with T12 paraplegia secondary to a motor vehicle accident in 1994. He called the primary clinic for a visit because he was concerned about cold clammy hands for the past 6 to 7 months when he woke up in the morning and sometimes throughout the day. He was preparing to start his first semester in college. His diagnosis included neurogenic bowel and bladder and muscle spasms. There was no history of posttraumatic syringomyelia, and his medications included baclofen, dantrolene, diazepam, and multivitamins.
Mr. B took tolterodine 4 mg/d for several years, and for unknown reasons, about 6 years previously the prescription was changed to oxybutynin 15-mg extended release for his neurogenic bladder. He continued to have urinary leakage between the every 4-hour intermittent catherization, and oxybutynin was increased to 10-mg tablet twice per day.
About 7 months prior to this appointment, Mr. B independently stopped the oxybutynin as he felt that it was not making a difference in the management of his neurogenic bladder. It was noted that his cold clammy hands started about the same time that he discontinued the oxybutynin. He could not recall whether he had this symptom prior to initiation of any medication. It was mutually decided to restart the oxybutynin at a lower dose, this time not for his bladder but for the HH. He was ordered a 30-day trial of a 5-mg tablet once per day. About 3 weeks later, he sent a secure message to report oxybutynin’s effectiveness and to request a refill.
Discussion
Sweating is a physiological process that involves the active secretion of water by specialized sweat glands in the skin.9-11 There are 2 types of sweat glands in the skin; apocrine and eccrine.9 Collectively the 3 million eccrine sweat glands of the average person approximately equal the mass of a kidney and exceed the secretory rate of exocrine glands.9 They function in evaporative cooling in response to thermal or physiologic stimuli and are widely distributed over the body, especially on the forehead, back, palms, and soles.10
Sympathetic cholinergic nerves are mainly responsible for sweat secretion by the release of acetylcholine to activate muscarinic receptors on the gland.11 Postganglionic fibers from sympathetic nerve cells innervate sweat glands that release cholinergics.6 Postganglionic cholinergic receptors that are activated by muscarinic drugs are termed muscarinic receptors and are readily accessible to antimuscarinic drugs.6,12 Anticholinergic/antimuscarinic agents antagonize muscarinic receptors and suppress premature detrusor contractions to enhance bladder storage.13 They include oxybutynin, tolterodine, trospium, solifenacin, darifenacin, and fesoterodine.13 Oxybutynin was used in both cases because it is on VA formulary. It was effective in treating HH, although the etiology is unclear and the presentations were different.
One retrospective study that analyzed 20 patients who received oxybutynin for primary HH at uncommon sites, such as the back and groin, found that QOL improved in 85% of the subjects after 6 weeks.14 Randomized placebo-controlled trials also have found oxybutynin effective for treatment of palmar and axillary HH and generalized HH.15,16
Syringomyelia was ruled out in both cases based on history and radiologic studies, specifically magnetic resonance imaging. Autonomic dysreflexia was ruled out as the HH was not an acute finding and BP was within normal limits. Orthostatic hypotension is a common finding in SCI, mainly in tetraplegic patients, and could be suspected in both cases. Sweating was usually worse in the mornings in both cases and during transfers, as noted in the first case.17 However, chronic autoregulation allows for chronic adaption to tissue hypoperfusion over time.16
Hyperhidrosis or other disorders of eccrine sweating can occur for various reasons, including changes in the spinal sympathetic preganglionic, ganglionic, or postganglionic neurons; dysfunction of the thermoregulatory centers in the brain’s central autonomic network; or changes in the muscarinic cholinergic synapse on sweat glands.18
Conclusion
Patients with SCI may have an acute or chronic presentation of HH. Removal of the inciting cause in the case of autonomic dysreflexia and/or the administration of a pharmaceutical agent is the usual treatment.
Regardless of the etiology of HH that persists, effective treatment should be a goal, especially in those patients whose QOL is affected by this condition. The outcome of treatment with oxybutynin in these case reports is consistent with the findings of the limited retrospective study and randomized placebo-controlled studies that show oxybutynin is effective for treating bothersome HH.14-16
The results of these case reports are not generalizable to patients with SCI and HH, nor are the results of the limited retrospective study and randomized placebo-controlled studies, as their sample sizes were small.14,16,17 However, information on the use of oxybutynin for the effective treatment of HH in the SCI population is promising. Research studies on the prevalence of HH and randomized placebo-controlled trials with a larger SCI population are considerations for future studies.
1. Strutton DR, Kowalski JW, Glaser DA, Stang PE. US prevalence of hyperhidrosis and impact on individuals with axillary hyperhidrosis: results from a national survey. J Am Acad Dermatol. 2004;51(2):241-248.
2. Walling HW. Clinical differentiation of primary from secondary hyperhidrosis. J Am Acad Dermatol. 2011;64(4):690-695.
3. Andersen LS, Biering-Sørensen F, Müller PG, Jensen IL, Aggerbeck B. The prevalence of hyperhidrosis in patients with spinal cord injuries and an evaluation of the effect of dextropropoxyphene hydrochloride in therapy. Paraplegia. 1992;(30):184-191.
4. Sato K, Kang WH, Saga K, Sato KT. Biology of sweat glands and their disorders. II. Disorders of sweat gland function. J Am Acad Dermatol. 1989;20(5, pt 1):713-726.
5. Kewalramani LS. Autonomic dysreflexia in traumatic myelopathy. Am J Phys Med. 1980;59(1):1-21.
6. Low PA, Engstrom JW. Disorders of the autonomic nervous system. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015.
7. Milhort TH. Classification of syringomyelia. Neurosurg Focus. 2000;8(3):E1.
8. National Institute of Neurological Disorders and Stroke. Syringomyelia fact sheet. https://www.ninds .nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Syringomyelia-Fact-Sheet. Accessed February 13, 2017.
9. Meschner AL. Junqueira’s Basic Histology. 14th ed. New York, NY: McGraw-Hill; 2016:371-392.
10. Mauro TM. Biology of eccrine and apocrine glands. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012.
11. Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical Physiology. 25th ed. New York, NY: McGraw-Hill; 2016:261-272.
12. Kellogg DL Jr. Thermoregulation. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012.
13. Rovner ES, Wyman J, Lam S. Urinary Incontinence. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill; 2014:1377-1396.
14. Teivelis MP, Wolosker N, Krutman M, Kauffman P, Campos JR, Puech-Leão P. Treatment of uncommon sites of focal primary hyperhidrosis: experience with pharmacological therapy using oxybutynin. Clinics (Sao Paulo). 2014;69(9):608-614.
15. Wolosker N, de Campos JR, Kauffman P, Puech-Leão P. A randomized-placebo-controlled trial of oxybutynin for the initial treatment of palmar and axillary hyperhidrosis. J Vasc Surg. 2012;55(6):1696-1700.
16. Schollhammer M, Brenaut E, Menard-Andivot N, et al. Oxybutynin as a treatment for generalized hyperhidrosis. Br J Dermatol. 2015;173(5):1163-1168.
17. Gonzalez F, Chang JY, Banovac K, Messina D, Martinez-Arizala A, Kelley RE. Autoregulation of cerebral blood flow in patients with orthostatic hypotension after spinal cord injury. Paraplegia. 1991;29(1):1-7.
18. Fealey RD, Hebert AA. Disorders of the eccrine sweat glands and sweating. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick’s Dermatology in General Medicine. New York, NY: McGraw-Hill; 2012:chap 84.
1. Strutton DR, Kowalski JW, Glaser DA, Stang PE. US prevalence of hyperhidrosis and impact on individuals with axillary hyperhidrosis: results from a national survey. J Am Acad Dermatol. 2004;51(2):241-248.
2. Walling HW. Clinical differentiation of primary from secondary hyperhidrosis. J Am Acad Dermatol. 2011;64(4):690-695.
3. Andersen LS, Biering-Sørensen F, Müller PG, Jensen IL, Aggerbeck B. The prevalence of hyperhidrosis in patients with spinal cord injuries and an evaluation of the effect of dextropropoxyphene hydrochloride in therapy. Paraplegia. 1992;(30):184-191.
4. Sato K, Kang WH, Saga K, Sato KT. Biology of sweat glands and their disorders. II. Disorders of sweat gland function. J Am Acad Dermatol. 1989;20(5, pt 1):713-726.
5. Kewalramani LS. Autonomic dysreflexia in traumatic myelopathy. Am J Phys Med. 1980;59(1):1-21.
6. Low PA, Engstrom JW. Disorders of the autonomic nervous system. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015.
7. Milhort TH. Classification of syringomyelia. Neurosurg Focus. 2000;8(3):E1.
8. National Institute of Neurological Disorders and Stroke. Syringomyelia fact sheet. https://www.ninds .nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Syringomyelia-Fact-Sheet. Accessed February 13, 2017.
9. Meschner AL. Junqueira’s Basic Histology. 14th ed. New York, NY: McGraw-Hill; 2016:371-392.
10. Mauro TM. Biology of eccrine and apocrine glands. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012.
11. Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical Physiology. 25th ed. New York, NY: McGraw-Hill; 2016:261-272.
12. Kellogg DL Jr. Thermoregulation. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012.
13. Rovner ES, Wyman J, Lam S. Urinary Incontinence. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill; 2014:1377-1396.
14. Teivelis MP, Wolosker N, Krutman M, Kauffman P, Campos JR, Puech-Leão P. Treatment of uncommon sites of focal primary hyperhidrosis: experience with pharmacological therapy using oxybutynin. Clinics (Sao Paulo). 2014;69(9):608-614.
15. Wolosker N, de Campos JR, Kauffman P, Puech-Leão P. A randomized-placebo-controlled trial of oxybutynin for the initial treatment of palmar and axillary hyperhidrosis. J Vasc Surg. 2012;55(6):1696-1700.
16. Schollhammer M, Brenaut E, Menard-Andivot N, et al. Oxybutynin as a treatment for generalized hyperhidrosis. Br J Dermatol. 2015;173(5):1163-1168.
17. Gonzalez F, Chang JY, Banovac K, Messina D, Martinez-Arizala A, Kelley RE. Autoregulation of cerebral blood flow in patients with orthostatic hypotension after spinal cord injury. Paraplegia. 1991;29(1):1-7.
18. Fealey RD, Hebert AA. Disorders of the eccrine sweat glands and sweating. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick’s Dermatology in General Medicine. New York, NY: McGraw-Hill; 2012:chap 84.
Imatinib is safe, effective long-term, team says
Long-term follow-up of patients treated with imatinib suggests the drug can remain effective beyond 10 years and does not confer “unacceptable” cumulative toxicity, according to researchers.
The group evaluated data on patients who had newly diagnosed, chronic-phase chronic myeloid leukemia (CML) when they began treatment with imatinib.
The median treatment duration was 8.9 years, and the estimated 10-year survival rate ranged from 64.4% to 84.4%.
The researchers said serious adverse events (AEs) thought to be related to imatinib were uncommon and typically occurred early, within the first year of treatment.
These results were reported in NEJM. The research was funded by Novartis Pharmaceuticals, which markets imatinib as Gleevec.
“The long-term success of this treatment confirms the remarkable success we’ve seen since the very first Gleevec trials,” said study author Brian Druker, MD, a physician-scientist at Oregon Health & Science University in Portland, Oregon, who led the original clinical development of Gleevec.
“This study reinforces the notion that we can create effective and non-toxic therapies.”
The study enrolled 1106 newly diagnosed, chronic-phase CML patients at 177 cancer centers in more than 16 countries. Half were assigned to treatment with imatinib (n=533) and the other half to interferon alfa plus cytarabine.
This study allowed for cross-over between the treatment arms, and 65.6% of patients in the cytarabine/interferon alfa arm ultimately crossed over to the imatinib arm.
However, when assessing the effects of imatinib, the researchers focused only on the patients who were first randomized to receive imatinib.
The median follow-up was 10.9 years (range, 0 to 11.7, which included follow-up after patients discontinued study treatment).
Of the patients randomized to imatinib, 48.3% (n=267) completed treatment with the drug. The median duration of first-line imatinib was 8.9 years (range, <0.1 to 11.7).
For patients who did not complete imatinib treatment, reasons for discontinuation included a lack of efficacy (15.9%), withdrawn consent (10.3%), AEs (6.9%), because they proceeded to transplant (3.8%), death (3.4%), protocol violation (3.1%), loss to follow-up (2.7%), cross over to the interferon arm (2.5%), administrative problems (2.2%), abnormal laboratory values (0.5%), or abnormal procedure (0.4%).
Safety
The incidence of serious AEs considered related to imatinib was 9.3% (51/551).
Drug-related serious AEs occurring in at least 2 patients included abdominal pain (n=4), anemia (n=3), congestive cardiac failure (n=3), gastrointestinal hemorrhage (n=3), vomiting (n=3), alanine aminotransferase increase (n=2), cardiac arrest (n=2), conjunctival hemorrhage (n=2), and melana (n=2).
Six patients had a second neoplasm (benign, malignant, or unspecified).
Response
The cumulative rate of complete cytogenetic response (CCR) at the end of the trial was 82.8%.
In the intent-to-treat population, the rate of CCR went from 52.8% in the first year to 22.2% at year 10.
Among evaluable patients, the rate of CCR went from 70.9% (292/412) in the first year to 91.8% (123/134) in year 10.
In the intent-to-treat population, the rate of major molecular response went from 27.7% in the first year to 34.4% at year 10.
Among evaluable patients, the rate of major molecular response went from 50.2% (153/305) in the first year to 93.1% (190/204) in year 10.
Progression and survival
The rate of progression was 6.9% (38/553) in the intent-to-treat population. Most of these patients (n=34) progressed during the first 4 years.
There were 260 patients who were still alive and receiving imatinib at 10 years and 96 patients who were alive but not receiving imatinib.
The researchers did not know the survival status of 111 patients, and there were 86 known deaths at 10 years (89 by the end of the study).
The estimated 10-year survival rate ranged from 64.4% (assuming all 111 patients with unknown status had died) to 84.4% (assuming all 111 were alive).
The cause of death was CML in 50 patients, a secondary malignant condition in 11, a cardiac disorder/cardiovascular disease in 7, infectious disease in 5, and “other” causes in 16 patients. 
Long-term follow-up of patients treated with imatinib suggests the drug can remain effective beyond 10 years and does not confer “unacceptable” cumulative toxicity, according to researchers.
The group evaluated data on patients who had newly diagnosed, chronic-phase chronic myeloid leukemia (CML) when they began treatment with imatinib.
The median treatment duration was 8.9 years, and the estimated 10-year survival rate ranged from 64.4% to 84.4%.
The researchers said serious adverse events (AEs) thought to be related to imatinib were uncommon and typically occurred early, within the first year of treatment.
These results were reported in NEJM. The research was funded by Novartis Pharmaceuticals, which markets imatinib as Gleevec.
“The long-term success of this treatment confirms the remarkable success we’ve seen since the very first Gleevec trials,” said study author Brian Druker, MD, a physician-scientist at Oregon Health & Science University in Portland, Oregon, who led the original clinical development of Gleevec.
“This study reinforces the notion that we can create effective and non-toxic therapies.”
The study enrolled 1106 newly diagnosed, chronic-phase CML patients at 177 cancer centers in more than 16 countries. Half were assigned to treatment with imatinib (n=533) and the other half to interferon alfa plus cytarabine.
This study allowed for cross-over between the treatment arms, and 65.6% of patients in the cytarabine/interferon alfa arm ultimately crossed over to the imatinib arm.
However, when assessing the effects of imatinib, the researchers focused only on the patients who were first randomized to receive imatinib.
The median follow-up was 10.9 years (range, 0 to 11.7, which included follow-up after patients discontinued study treatment).
Of the patients randomized to imatinib, 48.3% (n=267) completed treatment with the drug. The median duration of first-line imatinib was 8.9 years (range, <0.1 to 11.7).
For patients who did not complete imatinib treatment, reasons for discontinuation included a lack of efficacy (15.9%), withdrawn consent (10.3%), AEs (6.9%), because they proceeded to transplant (3.8%), death (3.4%), protocol violation (3.1%), loss to follow-up (2.7%), cross over to the interferon arm (2.5%), administrative problems (2.2%), abnormal laboratory values (0.5%), or abnormal procedure (0.4%).
Safety
The incidence of serious AEs considered related to imatinib was 9.3% (51/551).
Drug-related serious AEs occurring in at least 2 patients included abdominal pain (n=4), anemia (n=3), congestive cardiac failure (n=3), gastrointestinal hemorrhage (n=3), vomiting (n=3), alanine aminotransferase increase (n=2), cardiac arrest (n=2), conjunctival hemorrhage (n=2), and melana (n=2).
Six patients had a second neoplasm (benign, malignant, or unspecified).
Response
The cumulative rate of complete cytogenetic response (CCR) at the end of the trial was 82.8%.
In the intent-to-treat population, the rate of CCR went from 52.8% in the first year to 22.2% at year 10.
Among evaluable patients, the rate of CCR went from 70.9% (292/412) in the first year to 91.8% (123/134) in year 10.
In the intent-to-treat population, the rate of major molecular response went from 27.7% in the first year to 34.4% at year 10.
Among evaluable patients, the rate of major molecular response went from 50.2% (153/305) in the first year to 93.1% (190/204) in year 10.
Progression and survival
The rate of progression was 6.9% (38/553) in the intent-to-treat population. Most of these patients (n=34) progressed during the first 4 years.
There were 260 patients who were still alive and receiving imatinib at 10 years and 96 patients who were alive but not receiving imatinib.
The researchers did not know the survival status of 111 patients, and there were 86 known deaths at 10 years (89 by the end of the study).
The estimated 10-year survival rate ranged from 64.4% (assuming all 111 patients with unknown status had died) to 84.4% (assuming all 111 were alive).
The cause of death was CML in 50 patients, a secondary malignant condition in 11, a cardiac disorder/cardiovascular disease in 7, infectious disease in 5, and “other” causes in 16 patients.
Long-term follow-up of patients treated with imatinib suggests the drug can remain effective beyond 10 years and does not confer “unacceptable” cumulative toxicity, according to researchers.
The group evaluated data on patients who had newly diagnosed, chronic-phase chronic myeloid leukemia (CML) when they began treatment with imatinib.
The median treatment duration was 8.9 years, and the estimated 10-year survival rate ranged from 64.4% to 84.4%.
The researchers said serious adverse events (AEs) thought to be related to imatinib were uncommon and typically occurred early, within the first year of treatment.
These results were reported in NEJM. The research was funded by Novartis Pharmaceuticals, which markets imatinib as Gleevec.
“The long-term success of this treatment confirms the remarkable success we’ve seen since the very first Gleevec trials,” said study author Brian Druker, MD, a physician-scientist at Oregon Health & Science University in Portland, Oregon, who led the original clinical development of Gleevec.
“This study reinforces the notion that we can create effective and non-toxic therapies.”
The study enrolled 1106 newly diagnosed, chronic-phase CML patients at 177 cancer centers in more than 16 countries. Half were assigned to treatment with imatinib (n=533) and the other half to interferon alfa plus cytarabine.
This study allowed for cross-over between the treatment arms, and 65.6% of patients in the cytarabine/interferon alfa arm ultimately crossed over to the imatinib arm.
However, when assessing the effects of imatinib, the researchers focused only on the patients who were first randomized to receive imatinib.
The median follow-up was 10.9 years (range, 0 to 11.7, which included follow-up after patients discontinued study treatment).
Of the patients randomized to imatinib, 48.3% (n=267) completed treatment with the drug. The median duration of first-line imatinib was 8.9 years (range, <0.1 to 11.7).
For patients who did not complete imatinib treatment, reasons for discontinuation included a lack of efficacy (15.9%), withdrawn consent (10.3%), AEs (6.9%), because they proceeded to transplant (3.8%), death (3.4%), protocol violation (3.1%), loss to follow-up (2.7%), cross over to the interferon arm (2.5%), administrative problems (2.2%), abnormal laboratory values (0.5%), or abnormal procedure (0.4%).
Safety
The incidence of serious AEs considered related to imatinib was 9.3% (51/551).
Drug-related serious AEs occurring in at least 2 patients included abdominal pain (n=4), anemia (n=3), congestive cardiac failure (n=3), gastrointestinal hemorrhage (n=3), vomiting (n=3), alanine aminotransferase increase (n=2), cardiac arrest (n=2), conjunctival hemorrhage (n=2), and melana (n=2).
Six patients had a second neoplasm (benign, malignant, or unspecified).
Response
The cumulative rate of complete cytogenetic response (CCR) at the end of the trial was 82.8%.
In the intent-to-treat population, the rate of CCR went from 52.8% in the first year to 22.2% at year 10.
Among evaluable patients, the rate of CCR went from 70.9% (292/412) in the first year to 91.8% (123/134) in year 10.
In the intent-to-treat population, the rate of major molecular response went from 27.7% in the first year to 34.4% at year 10.
Among evaluable patients, the rate of major molecular response went from 50.2% (153/305) in the first year to 93.1% (190/204) in year 10.
Progression and survival
The rate of progression was 6.9% (38/553) in the intent-to-treat population. Most of these patients (n=34) progressed during the first 4 years.
There were 260 patients who were still alive and receiving imatinib at 10 years and 96 patients who were alive but not receiving imatinib.
The researchers did not know the survival status of 111 patients, and there were 86 known deaths at 10 years (89 by the end of the study).
The estimated 10-year survival rate ranged from 64.4% (assuming all 111 patients with unknown status had died) to 84.4% (assuming all 111 were alive).
The cause of death was CML in 50 patients, a secondary malignant condition in 11, a cardiac disorder/cardiovascular disease in 7, infectious disease in 5, and “other” causes in 16 patients.
Drug exhibits anti-myeloma activity in mice, humans
An experimental drug called LCL161 stimulates the immune system to fight multiple myeloma (MM), according to research published in Nature Medicine.
Investigators said LCL161 exhibited “robust” activity in a transgenic myeloma mouse model and in patients with relapsed/refractory MM.
Single-agent LCL161 did not produce responses in MM patients, but patients did respond to treatment with LCL161 and cyclophosphamide.
The investigators also found that single-agent LCL161 provided “long-term anti-tumor protection” in mice, and combining LCL161 with an antibody against PD-1 could cure mice of MM.
“The drug, LCL161, was initially developed to promote tumor death,” said study author Marta Chesi, PhD, of Mayo Clinic Arizona in Scottsdale.
“However, we found that the drug does not kill tumor cells directly. Rather, it makes them more visible to the immune system that recognizes them as foreign invaders and eliminates them.”
Dr Chesi and her colleagues explained that the cellular inhibitors of apoptosis (cIAP) 1 and 2 have been identified as potential therapeutic targets in some cancers.
And LCL161 is a small-molecule IAP antagonist that induces tumor necrosis factor-mediated apoptosis in cancer cells. However, the investigators found that LCL161 was not directly cytotoxic to MM cells.
Instead, the drug upregulated tumor-cell-autonomous type I interferon signaling and induced an acute inflammatory response. This led to the activation of macrophages and dendritic cells, which prompted phagocytosis in MM cells.
Results in mice
The investigators first tested LCL161 alone (at a dose previously shown to be well-tolerated) in Vk*MYC transgenic mice with established MM.
The team said they observed a reduction in tumor burden that was comparable to that observed in response to drugs currently used to treat MM—carfilzomib, bortezomib, melphalan, cyclophosphamide, panobinostat, dexamethasone, and pomalidomide.
The investigators then tested the combination of LCL161 and a PD1 antibody in Vk12598-tumor-bearing mice.
The team said the combination was curative in all mice that completed 2 weeks of treatment. In fact, it was more effective than combination treatment with LCL161 and cyclophosphamide.
Results in patients
Dr Chesi and her colleagues conducted a phase 2 trial of LCL161 in 25 patients with relapsed/refractory MM. Patients could receive cyclophosphamide if they failed to respond or progressed after 8 weeks of treatment with LCL161 alone.
The patients’ median age was 68 (range, 47-90), and they had a median of 3 prior therapies (range, 1-6). Forty-four percent of patients had high-risk features, 28% had relapsed disease, and 72% had relapsed and refractory disease.
Four patients experienced grade 2 cytokine release syndrome when they received LCL161 at a dose of 1800 mg weekly, so the dose was lowered to 1200 mg.
None of the patients responded to single-agent LCL161. So 23 of the patients received 500 mg of weekly cyclophosphamide as well.
There was 1 complete response to the combination therapy, 1 very good partial response, 2 partial responses, and 1 minimal response. The median progression-free survival in these patients was 10 months.
Grade 3 adverse events included decrease in neutrophil count (28%), decrease in lymphocyte count (28%), anemia (24%), fatigue (16%), hyperglycemia (12%), syncope (12%), decrease in white blood cell count (12%), decrease in platelet count (8%), increase in lymphocyte count (8%), nausea (4%), vomiting (4%), diarrhea (4%), maculo-papular rash (4%), hypotension (4%), lung infection (4%), pain in extremity (4%), and urticaria (4%).
Grade 4 events included decrease in lymphocyte count (24%), decrease in neutrophil count (8%), decrease in white blood cell count (8%), hyperuricemia (4%), decrease in platelet count (4%), and sepsis (4%).
Based on these results, the investigators said the combination of LCL161 and cyclophosphamide is “an attractive platform for future trials,” and the same is true for LCL161 in combination with anti-PD1 therapy.
The phase 2 trial was sponsored by Mayo Clinic and the National Cancer Institute. Novartis provided LCL161 for this research and supported the trial.
An experimental drug called LCL161 stimulates the immune system to fight multiple myeloma (MM), according to research published in Nature Medicine.
Investigators said LCL161 exhibited “robust” activity in a transgenic myeloma mouse model and in patients with relapsed/refractory MM.
Single-agent LCL161 did not produce responses in MM patients, but patients did respond to treatment with LCL161 and cyclophosphamide.
The investigators also found that single-agent LCL161 provided “long-term anti-tumor protection” in mice, and combining LCL161 with an antibody against PD-1 could cure mice of MM.
“The drug, LCL161, was initially developed to promote tumor death,” said study author Marta Chesi, PhD, of Mayo Clinic Arizona in Scottsdale.
“However, we found that the drug does not kill tumor cells directly. Rather, it makes them more visible to the immune system that recognizes them as foreign invaders and eliminates them.”
Dr Chesi and her colleagues explained that the cellular inhibitors of apoptosis (cIAP) 1 and 2 have been identified as potential therapeutic targets in some cancers.
And LCL161 is a small-molecule IAP antagonist that induces tumor necrosis factor-mediated apoptosis in cancer cells. However, the investigators found that LCL161 was not directly cytotoxic to MM cells.
Instead, the drug upregulated tumor-cell-autonomous type I interferon signaling and induced an acute inflammatory response. This led to the activation of macrophages and dendritic cells, which prompted phagocytosis in MM cells.
Results in mice
The investigators first tested LCL161 alone (at a dose previously shown to be well-tolerated) in Vk*MYC transgenic mice with established MM.
The team said they observed a reduction in tumor burden that was comparable to that observed in response to drugs currently used to treat MM—carfilzomib, bortezomib, melphalan, cyclophosphamide, panobinostat, dexamethasone, and pomalidomide.
The investigators then tested the combination of LCL161 and a PD1 antibody in Vk12598-tumor-bearing mice.
The team said the combination was curative in all mice that completed 2 weeks of treatment. In fact, it was more effective than combination treatment with LCL161 and cyclophosphamide.
Results in patients
Dr Chesi and her colleagues conducted a phase 2 trial of LCL161 in 25 patients with relapsed/refractory MM. Patients could receive cyclophosphamide if they failed to respond or progressed after 8 weeks of treatment with LCL161 alone.
The patients’ median age was 68 (range, 47-90), and they had a median of 3 prior therapies (range, 1-6). Forty-four percent of patients had high-risk features, 28% had relapsed disease, and 72% had relapsed and refractory disease.
Four patients experienced grade 2 cytokine release syndrome when they received LCL161 at a dose of 1800 mg weekly, so the dose was lowered to 1200 mg.
None of the patients responded to single-agent LCL161. So 23 of the patients received 500 mg of weekly cyclophosphamide as well.
There was 1 complete response to the combination therapy, 1 very good partial response, 2 partial responses, and 1 minimal response. The median progression-free survival in these patients was 10 months.
Grade 3 adverse events included decrease in neutrophil count (28%), decrease in lymphocyte count (28%), anemia (24%), fatigue (16%), hyperglycemia (12%), syncope (12%), decrease in white blood cell count (12%), decrease in platelet count (8%), increase in lymphocyte count (8%), nausea (4%), vomiting (4%), diarrhea (4%), maculo-papular rash (4%), hypotension (4%), lung infection (4%), pain in extremity (4%), and urticaria (4%).
Grade 4 events included decrease in lymphocyte count (24%), decrease in neutrophil count (8%), decrease in white blood cell count (8%), hyperuricemia (4%), decrease in platelet count (4%), and sepsis (4%).
Based on these results, the investigators said the combination of LCL161 and cyclophosphamide is “an attractive platform for future trials,” and the same is true for LCL161 in combination with anti-PD1 therapy.
The phase 2 trial was sponsored by Mayo Clinic and the National Cancer Institute. Novartis provided LCL161 for this research and supported the trial.
An experimental drug called LCL161 stimulates the immune system to fight multiple myeloma (MM), according to research published in Nature Medicine.
Investigators said LCL161 exhibited “robust” activity in a transgenic myeloma mouse model and in patients with relapsed/refractory MM.
Single-agent LCL161 did not produce responses in MM patients, but patients did respond to treatment with LCL161 and cyclophosphamide.
The investigators also found that single-agent LCL161 provided “long-term anti-tumor protection” in mice, and combining LCL161 with an antibody against PD-1 could cure mice of MM.
“The drug, LCL161, was initially developed to promote tumor death,” said study author Marta Chesi, PhD, of Mayo Clinic Arizona in Scottsdale.
“However, we found that the drug does not kill tumor cells directly. Rather, it makes them more visible to the immune system that recognizes them as foreign invaders and eliminates them.”
Dr Chesi and her colleagues explained that the cellular inhibitors of apoptosis (cIAP) 1 and 2 have been identified as potential therapeutic targets in some cancers.
And LCL161 is a small-molecule IAP antagonist that induces tumor necrosis factor-mediated apoptosis in cancer cells. However, the investigators found that LCL161 was not directly cytotoxic to MM cells.
Instead, the drug upregulated tumor-cell-autonomous type I interferon signaling and induced an acute inflammatory response. This led to the activation of macrophages and dendritic cells, which prompted phagocytosis in MM cells.
Results in mice
The investigators first tested LCL161 alone (at a dose previously shown to be well-tolerated) in Vk*MYC transgenic mice with established MM.
The team said they observed a reduction in tumor burden that was comparable to that observed in response to drugs currently used to treat MM—carfilzomib, bortezomib, melphalan, cyclophosphamide, panobinostat, dexamethasone, and pomalidomide.
The investigators then tested the combination of LCL161 and a PD1 antibody in Vk12598-tumor-bearing mice.
The team said the combination was curative in all mice that completed 2 weeks of treatment. In fact, it was more effective than combination treatment with LCL161 and cyclophosphamide.
Results in patients
Dr Chesi and her colleagues conducted a phase 2 trial of LCL161 in 25 patients with relapsed/refractory MM. Patients could receive cyclophosphamide if they failed to respond or progressed after 8 weeks of treatment with LCL161 alone.
The patients’ median age was 68 (range, 47-90), and they had a median of 3 prior therapies (range, 1-6). Forty-four percent of patients had high-risk features, 28% had relapsed disease, and 72% had relapsed and refractory disease.
Four patients experienced grade 2 cytokine release syndrome when they received LCL161 at a dose of 1800 mg weekly, so the dose was lowered to 1200 mg.
None of the patients responded to single-agent LCL161. So 23 of the patients received 500 mg of weekly cyclophosphamide as well.
There was 1 complete response to the combination therapy, 1 very good partial response, 2 partial responses, and 1 minimal response. The median progression-free survival in these patients was 10 months.
Grade 3 adverse events included decrease in neutrophil count (28%), decrease in lymphocyte count (28%), anemia (24%), fatigue (16%), hyperglycemia (12%), syncope (12%), decrease in white blood cell count (12%), decrease in platelet count (8%), increase in lymphocyte count (8%), nausea (4%), vomiting (4%), diarrhea (4%), maculo-papular rash (4%), hypotension (4%), lung infection (4%), pain in extremity (4%), and urticaria (4%).
Grade 4 events included decrease in lymphocyte count (24%), decrease in neutrophil count (8%), decrease in white blood cell count (8%), hyperuricemia (4%), decrease in platelet count (4%), and sepsis (4%).
Based on these results, the investigators said the combination of LCL161 and cyclophosphamide is “an attractive platform for future trials,” and the same is true for LCL161 in combination with anti-PD1 therapy.
The phase 2 trial was sponsored by Mayo Clinic and the National Cancer Institute. Novartis provided LCL161 for this research and supported the trial.
Transfusion practice may harm certain patients
A retrospective study indicates that a high transfusion ratio of fresh frozen plasma (FFP) to red blood cells (RBCs) may not be beneficial for surgical patients who do not have traumatic injuries.
In fact, the data suggest a high FFP:RBC ratio may be harmful for some of these patients.
“The strategy of giving patients requiring massive transfusion greater amounts of fresh frozen plasma, relative to the amount of red blood cells, has spilled over from trauma patients into unstudied patient populations,” said Daniel Dante Yeh, MD, of Massachusetts General Hospital in Boston.
“This may have important consequences, since our results suggest that certain populations may be harmed by this practice.”
Dr Yeh and his colleagues reported these results in JAMA Surgery.
The researchers reviewed all massive transfusions performed at Massachusetts General Hospital from January 1, 2009, through December 31, 2012.
A transfusion qualified as “massive” if at least 10 units of RBCs were given in the first 24 hours after a patient’s admission to the operating room, emergency department, or intensive care unit.
The researchers included all patients who received massive transfusions during the study period and survived more than 30 minutes after hospital arrival.
According to these criteria, there were 865 massive transfusion events. The total number of units transfused was 16,569 for RBCs, 13,933 for FFP, 5228 for cryoprecipitate, and 22,635 for platelets.
A majority of the massive transfusion recipients were not trauma patients (88.7%). Most of the transfusions were performed for intraoperative bleeding (62.9%).
The researchers compared patients who survived at least 30 days from hospital arrival to those who did not. Patients who died were older and received more RBCs (P<0.001), FFP (P<0.001), and cryoprecipitate (P=0.008).
However, the FFP:RBC ratios of survivors and non-survivors were similar. The median was 1:1.5 for survivors and 1:1.4 for non-survivors (P=0.43).
Patients without trauma
Among all non-trauma patients (n=767), there was no significant difference in the adjusted odds ratio (aOR) for 30-day mortality between patients who received a transfusion with a high FFP:RBC ratio and those who received one with a low FFP:RBC ratio (aOR=1.10, P=0.65). (The analysis was adjusted for patient age and total units of RBCs transfused.)
Among patients undergoing vascular surgery, those who received transfusions with a high FFP:RBC ratio were less likely to die within 30 days than those who received transfusions with a low FFP:RBC ratio (aOR=0.16, P=0.02).
However, among general surgery and medical service patients, those receiving transfusions with a high FFP:RBC ratio were more likely to die within 30 days than those receiving low-ratio transfusions. The aOR was 4.27 (P=0.02) for general surgery and 8.48 (P=0.02) for medicine.
“Finding evidence of increased mortality in some patients was surprising because that is directly contradictory to what is expected and intended,” Dr Yeh said. “Avoiding unnecessary FFP transfusion is important because there have been reports that associated the use of excess FFP with worse outcomes among patients that required less-than-massive transfusions.”
“Because our study is retrospective, it can only point to the need for further research. Ratio-based transfusion has been studied in trauma patients, most recently in a landmark, multicenter, randomized study called the PROPRR trial. Similar studies now need to be performed in non-trauma patients before the approach can be accepted as standard practice here at MGH [Massachusetts General Hospital] and elsewhere.”
A retrospective study indicates that a high transfusion ratio of fresh frozen plasma (FFP) to red blood cells (RBCs) may not be beneficial for surgical patients who do not have traumatic injuries.
In fact, the data suggest a high FFP:RBC ratio may be harmful for some of these patients.
“The strategy of giving patients requiring massive transfusion greater amounts of fresh frozen plasma, relative to the amount of red blood cells, has spilled over from trauma patients into unstudied patient populations,” said Daniel Dante Yeh, MD, of Massachusetts General Hospital in Boston.
“This may have important consequences, since our results suggest that certain populations may be harmed by this practice.”
Dr Yeh and his colleagues reported these results in JAMA Surgery.
The researchers reviewed all massive transfusions performed at Massachusetts General Hospital from January 1, 2009, through December 31, 2012.
A transfusion qualified as “massive” if at least 10 units of RBCs were given in the first 24 hours after a patient’s admission to the operating room, emergency department, or intensive care unit.
The researchers included all patients who received massive transfusions during the study period and survived more than 30 minutes after hospital arrival.
According to these criteria, there were 865 massive transfusion events. The total number of units transfused was 16,569 for RBCs, 13,933 for FFP, 5228 for cryoprecipitate, and 22,635 for platelets.
A majority of the massive transfusion recipients were not trauma patients (88.7%). Most of the transfusions were performed for intraoperative bleeding (62.9%).
The researchers compared patients who survived at least 30 days from hospital arrival to those who did not. Patients who died were older and received more RBCs (P<0.001), FFP (P<0.001), and cryoprecipitate (P=0.008).
However, the FFP:RBC ratios of survivors and non-survivors were similar. The median was 1:1.5 for survivors and 1:1.4 for non-survivors (P=0.43).
Patients without trauma
Among all non-trauma patients (n=767), there was no significant difference in the adjusted odds ratio (aOR) for 30-day mortality between patients who received a transfusion with a high FFP:RBC ratio and those who received one with a low FFP:RBC ratio (aOR=1.10, P=0.65). (The analysis was adjusted for patient age and total units of RBCs transfused.)
Among patients undergoing vascular surgery, those who received transfusions with a high FFP:RBC ratio were less likely to die within 30 days than those who received transfusions with a low FFP:RBC ratio (aOR=0.16, P=0.02).
However, among general surgery and medical service patients, those receiving transfusions with a high FFP:RBC ratio were more likely to die within 30 days than those receiving low-ratio transfusions. The aOR was 4.27 (P=0.02) for general surgery and 8.48 (P=0.02) for medicine.
“Finding evidence of increased mortality in some patients was surprising because that is directly contradictory to what is expected and intended,” Dr Yeh said. “Avoiding unnecessary FFP transfusion is important because there have been reports that associated the use of excess FFP with worse outcomes among patients that required less-than-massive transfusions.”
“Because our study is retrospective, it can only point to the need for further research. Ratio-based transfusion has been studied in trauma patients, most recently in a landmark, multicenter, randomized study called the PROPRR trial. Similar studies now need to be performed in non-trauma patients before the approach can be accepted as standard practice here at MGH [Massachusetts General Hospital] and elsewhere.”
A retrospective study indicates that a high transfusion ratio of fresh frozen plasma (FFP) to red blood cells (RBCs) may not be beneficial for surgical patients who do not have traumatic injuries.
In fact, the data suggest a high FFP:RBC ratio may be harmful for some of these patients.
“The strategy of giving patients requiring massive transfusion greater amounts of fresh frozen plasma, relative to the amount of red blood cells, has spilled over from trauma patients into unstudied patient populations,” said Daniel Dante Yeh, MD, of Massachusetts General Hospital in Boston.
“This may have important consequences, since our results suggest that certain populations may be harmed by this practice.”
Dr Yeh and his colleagues reported these results in JAMA Surgery.
The researchers reviewed all massive transfusions performed at Massachusetts General Hospital from January 1, 2009, through December 31, 2012.
A transfusion qualified as “massive” if at least 10 units of RBCs were given in the first 24 hours after a patient’s admission to the operating room, emergency department, or intensive care unit.
The researchers included all patients who received massive transfusions during the study period and survived more than 30 minutes after hospital arrival.
According to these criteria, there were 865 massive transfusion events. The total number of units transfused was 16,569 for RBCs, 13,933 for FFP, 5228 for cryoprecipitate, and 22,635 for platelets.
A majority of the massive transfusion recipients were not trauma patients (88.7%). Most of the transfusions were performed for intraoperative bleeding (62.9%).
The researchers compared patients who survived at least 30 days from hospital arrival to those who did not. Patients who died were older and received more RBCs (P<0.001), FFP (P<0.001), and cryoprecipitate (P=0.008).
However, the FFP:RBC ratios of survivors and non-survivors were similar. The median was 1:1.5 for survivors and 1:1.4 for non-survivors (P=0.43).
Patients without trauma
Among all non-trauma patients (n=767), there was no significant difference in the adjusted odds ratio (aOR) for 30-day mortality between patients who received a transfusion with a high FFP:RBC ratio and those who received one with a low FFP:RBC ratio (aOR=1.10, P=0.65). (The analysis was adjusted for patient age and total units of RBCs transfused.)
Among patients undergoing vascular surgery, those who received transfusions with a high FFP:RBC ratio were less likely to die within 30 days than those who received transfusions with a low FFP:RBC ratio (aOR=0.16, P=0.02).
However, among general surgery and medical service patients, those receiving transfusions with a high FFP:RBC ratio were more likely to die within 30 days than those receiving low-ratio transfusions. The aOR was 4.27 (P=0.02) for general surgery and 8.48 (P=0.02) for medicine.
“Finding evidence of increased mortality in some patients was surprising because that is directly contradictory to what is expected and intended,” Dr Yeh said. “Avoiding unnecessary FFP transfusion is important because there have been reports that associated the use of excess FFP with worse outcomes among patients that required less-than-massive transfusions.”
“Because our study is retrospective, it can only point to the need for further research. Ratio-based transfusion has been studied in trauma patients, most recently in a landmark, multicenter, randomized study called the PROPRR trial. Similar studies now need to be performed in non-trauma patients before the approach can be accepted as standard practice here at MGH [Massachusetts General Hospital] and elsewhere.”
FDA lifts clinical hold on AML trials
The US Food and Drug Administration (FDA) has lifted the clinical hold placed on 3 trials of vadastuximab talirine (SGN-CD33A), an antibody-drug conjugate targeting CD33, in acute myeloid leukemia (AML).
Last December, 1 trial was placed on full clinical hold (enrollment was halted and no further dosing of subjects was allowed), and 2 were placed on partial hold (enrollment was halted, but existing patients could continue treatment with re-consent).
All 3 of the holds were due to the potential risk of hepatotoxicity in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) before or after treatment with vadastuximab talirine.
In particular, the holds were in response to 6 cases of hepatotoxicity, including several cases of veno-occlusive disease (VOD), with 4 fatal events.
At the time the holds were announced, Seattle Genetics, Inc., the company developing vadastuximab talirine, said it was working with the FDA to determine whether there is an association between hepatotoxicity and treatment with the drug.
The company analyzed data from more than 350 patients treated with vadastuximab talirine and found no such association.
The rate of VOD they observed was “within the background rate of VOD in AML patients receiving allo-transplant,” according to Clay B. Siegall, PhD, president, chief executive officer, and chairman of the board at Seattle Genetics.
Dr Siegall said the company would not disclose the exact rate of VOD in these trials.
Resuming trials
As Seattle Genetics found no evidence to suggest that vadastuximab talirine increased the risk of hepatotoxicity, the FDA lifted the clinical holds on all 3 trials. The 2 trials placed on partial hold will continue, but the trial placed on full hold will not.
One of the trials that will continue is a phase 1 study of vadastuximab talirine alone and in combination with hypomethylating agents in both newly diagnosed and relapsed AML patients.
The other trial is a phase 1 study of vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients. (Results from this trial were presented at the 2016 ASH Annual Meeting.)
Cancelled trial
The trial that will not resume is a phase 1/2 study of vadastuximab talirine monotherapy pre- and post-allogeneic HSCT in patients with relapsed, chemo-resistant AML.
Seattle Genetics said it will not continue with this trial because of the challenges of developing therapies in this specific setting.
“It’s a very small group of patients, and we’re going to focus on the 3 biggest groups of patients [older and younger patients newly diagnosed with AML and patients with myelodysplastic syndromes] so we can really impact AML in the biggest way,” Dr Siegall said.
He noted that this decision does not prevent patients from undergoing HSCT after receiving vadastuximab talirine.
In the phase 1/2 trial, patients received vadastuximab talirine directly before HSCT, a practice that will not continue. However, patients can undergo HSCT as long as the transplant doesn’t occur immediately after treatment with vadastuximab talirine.
Moving forward
Two other trials of vadastuximab talirine were not affected by the clinical holds and have continued to enroll patients.
One is CASCADE, a randomized, phase 3 trial of vadastuximab talirine as front-line therapy in older AML patients. The other is a phase 1/2 trial of vadastuximab talirine as front-line therapy in patients with myelodysplastic syndromes.
Seattle Genetics is also planning to begin a randomized, phase 2 trial comparing 7+3 chemotherapy alone to 7+3 in combination with vadastuximab talirine in younger patients with previously untreated AML. The company plans to start the trial later this year.
Going forward, additional risk mitigation measures will be implemented in all vadastuximab talirine studies, including revised eligibility criteria and stopping rules for VOD.
Specifically, trials will not be stopped if the incidence of VOD is considered within the normal range, and an adjudication committee consisting of 2 experts will be tasked with verifying reports of VOD.
In addition, patients with liver cirrhosis due to alcohol abuse are no longer eligible for trials of vadastuximab talirine.
The US Food and Drug Administration (FDA) has lifted the clinical hold placed on 3 trials of vadastuximab talirine (SGN-CD33A), an antibody-drug conjugate targeting CD33, in acute myeloid leukemia (AML).
Last December, 1 trial was placed on full clinical hold (enrollment was halted and no further dosing of subjects was allowed), and 2 were placed on partial hold (enrollment was halted, but existing patients could continue treatment with re-consent).
All 3 of the holds were due to the potential risk of hepatotoxicity in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) before or after treatment with vadastuximab talirine.
In particular, the holds were in response to 6 cases of hepatotoxicity, including several cases of veno-occlusive disease (VOD), with 4 fatal events.
At the time the holds were announced, Seattle Genetics, Inc., the company developing vadastuximab talirine, said it was working with the FDA to determine whether there is an association between hepatotoxicity and treatment with the drug.
The company analyzed data from more than 350 patients treated with vadastuximab talirine and found no such association.
The rate of VOD they observed was “within the background rate of VOD in AML patients receiving allo-transplant,” according to Clay B. Siegall, PhD, president, chief executive officer, and chairman of the board at Seattle Genetics.
Dr Siegall said the company would not disclose the exact rate of VOD in these trials.
Resuming trials
As Seattle Genetics found no evidence to suggest that vadastuximab talirine increased the risk of hepatotoxicity, the FDA lifted the clinical holds on all 3 trials. The 2 trials placed on partial hold will continue, but the trial placed on full hold will not.
One of the trials that will continue is a phase 1 study of vadastuximab talirine alone and in combination with hypomethylating agents in both newly diagnosed and relapsed AML patients.
The other trial is a phase 1 study of vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients. (Results from this trial were presented at the 2016 ASH Annual Meeting.)
Cancelled trial
The trial that will not resume is a phase 1/2 study of vadastuximab talirine monotherapy pre- and post-allogeneic HSCT in patients with relapsed, chemo-resistant AML.
Seattle Genetics said it will not continue with this trial because of the challenges of developing therapies in this specific setting.
“It’s a very small group of patients, and we’re going to focus on the 3 biggest groups of patients [older and younger patients newly diagnosed with AML and patients with myelodysplastic syndromes] so we can really impact AML in the biggest way,” Dr Siegall said.
He noted that this decision does not prevent patients from undergoing HSCT after receiving vadastuximab talirine.
In the phase 1/2 trial, patients received vadastuximab talirine directly before HSCT, a practice that will not continue. However, patients can undergo HSCT as long as the transplant doesn’t occur immediately after treatment with vadastuximab talirine.
Moving forward
Two other trials of vadastuximab talirine were not affected by the clinical holds and have continued to enroll patients.
One is CASCADE, a randomized, phase 3 trial of vadastuximab talirine as front-line therapy in older AML patients. The other is a phase 1/2 trial of vadastuximab talirine as front-line therapy in patients with myelodysplastic syndromes.
Seattle Genetics is also planning to begin a randomized, phase 2 trial comparing 7+3 chemotherapy alone to 7+3 in combination with vadastuximab talirine in younger patients with previously untreated AML. The company plans to start the trial later this year.
Going forward, additional risk mitigation measures will be implemented in all vadastuximab talirine studies, including revised eligibility criteria and stopping rules for VOD.
Specifically, trials will not be stopped if the incidence of VOD is considered within the normal range, and an adjudication committee consisting of 2 experts will be tasked with verifying reports of VOD.
In addition, patients with liver cirrhosis due to alcohol abuse are no longer eligible for trials of vadastuximab talirine.
The US Food and Drug Administration (FDA) has lifted the clinical hold placed on 3 trials of vadastuximab talirine (SGN-CD33A), an antibody-drug conjugate targeting CD33, in acute myeloid leukemia (AML).
Last December, 1 trial was placed on full clinical hold (enrollment was halted and no further dosing of subjects was allowed), and 2 were placed on partial hold (enrollment was halted, but existing patients could continue treatment with re-consent).
All 3 of the holds were due to the potential risk of hepatotoxicity in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) before or after treatment with vadastuximab talirine.
In particular, the holds were in response to 6 cases of hepatotoxicity, including several cases of veno-occlusive disease (VOD), with 4 fatal events.
At the time the holds were announced, Seattle Genetics, Inc., the company developing vadastuximab talirine, said it was working with the FDA to determine whether there is an association between hepatotoxicity and treatment with the drug.
The company analyzed data from more than 350 patients treated with vadastuximab talirine and found no such association.
The rate of VOD they observed was “within the background rate of VOD in AML patients receiving allo-transplant,” according to Clay B. Siegall, PhD, president, chief executive officer, and chairman of the board at Seattle Genetics.
Dr Siegall said the company would not disclose the exact rate of VOD in these trials.
Resuming trials
As Seattle Genetics found no evidence to suggest that vadastuximab talirine increased the risk of hepatotoxicity, the FDA lifted the clinical holds on all 3 trials. The 2 trials placed on partial hold will continue, but the trial placed on full hold will not.
One of the trials that will continue is a phase 1 study of vadastuximab talirine alone and in combination with hypomethylating agents in both newly diagnosed and relapsed AML patients.
The other trial is a phase 1 study of vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients. (Results from this trial were presented at the 2016 ASH Annual Meeting.)
Cancelled trial
The trial that will not resume is a phase 1/2 study of vadastuximab talirine monotherapy pre- and post-allogeneic HSCT in patients with relapsed, chemo-resistant AML.
Seattle Genetics said it will not continue with this trial because of the challenges of developing therapies in this specific setting.
“It’s a very small group of patients, and we’re going to focus on the 3 biggest groups of patients [older and younger patients newly diagnosed with AML and patients with myelodysplastic syndromes] so we can really impact AML in the biggest way,” Dr Siegall said.
He noted that this decision does not prevent patients from undergoing HSCT after receiving vadastuximab talirine.
In the phase 1/2 trial, patients received vadastuximab talirine directly before HSCT, a practice that will not continue. However, patients can undergo HSCT as long as the transplant doesn’t occur immediately after treatment with vadastuximab talirine.
Moving forward
Two other trials of vadastuximab talirine were not affected by the clinical holds and have continued to enroll patients.
One is CASCADE, a randomized, phase 3 trial of vadastuximab talirine as front-line therapy in older AML patients. The other is a phase 1/2 trial of vadastuximab talirine as front-line therapy in patients with myelodysplastic syndromes.
Seattle Genetics is also planning to begin a randomized, phase 2 trial comparing 7+3 chemotherapy alone to 7+3 in combination with vadastuximab talirine in younger patients with previously untreated AML. The company plans to start the trial later this year.
Going forward, additional risk mitigation measures will be implemented in all vadastuximab talirine studies, including revised eligibility criteria and stopping rules for VOD.
Specifically, trials will not be stopped if the incidence of VOD is considered within the normal range, and an adjudication committee consisting of 2 experts will be tasked with verifying reports of VOD.
In addition, patients with liver cirrhosis due to alcohol abuse are no longer eligible for trials of vadastuximab talirine.
Trump travel policy may affect medical meetings
President Trump’s revised executive order blocking travelers from six Muslim-majority countries from entering the United States could land a damaging blow to global cooperation in scientific research and could impede assemblies of the world’s top medical experts.
The March 6 executive order bars citizens of Iran, Libya, Somalia, Sudan, Syria, and Yemen from obtaining visas for 90 days and blocks refugees from those countries from entering the United States for 120 days. The measure, which takes effect March 16, supersedes President Trump’s original Jan. 27 travel ban. The new order exempts citizens of the six countries who are legal permanent U.S. residents or who have current visas.
The policy could have detrimental effects on future collaboration between U.S. and international scientists and may ultimately endanger the health and well-being of patients, said International Antiviral Society–U.S.A. executive director and president Donna M. Jacobsen, regarding the original travel ban.
There is “serious reason for concern” that the policy will dissuade scientists and researchers “from traveling to the [United States] in the future overall and sharing their work with colleagues here,” she said.
Thousands of academics from around the world, including physicians, researchers, and professors, have vowed to boycott U.S.-based conferences in light of the Trump administration policy. A Google Docs petition started shortly after the original ban was announced garnered more than 5,000 signatures by professionals acting in solidarity with those affected by the travel restrictions. The academicians who signed the petition said they would not attend international conferences in the United States until those restricted from participating could rejoin their colleagues and freely share their ideas.
The new executive order comes nearly 2 months after President Trump’s original travel ban caused nationwide protests and led to a series of legal challenges. The states of Washington and Minnesota, which sued President Trump over his original ban, argued that such a ban harms the teaching and research missions of their universities and prevents students and faculty from traveling for research and academic collaboration. In addition, the executive order restricts universities from hiring attractive candidates from countries affected by the ban, state officials said. A federal court temporarily blocked the original travel ban on Feb. 3, a decision upheld by the 9th U.S. Circuit Court of Appeals on Feb. 9. The circuit judges said the plaintiffs were likely to succeed in their arguments and that the president had demonstrated no evidence that his executive order advances national security.
The new executive order excludes Iraq and also removes language that had indefinitely banned Syrian refugees. In a March 6 memorandum, the White House said the purpose of the ban is to prevent “foreign nationals who may aid, support, or commit violent, criminal, or terrorist acts,” while the administration enhances the screening and vetting protocols and procedures for granting visas and admission to the United States.
“This nation cannot delay the immediate implementation of additional heightened screening and vetting protocols and procedures for issuing visas to ensure that we strengthen the safety and security of our country,” the memo states.
[email protected]
On Twitter @legal_med
February 7, 2017
The Honorable John F. Kelly
Secretary
U.S. Department of Homeland Security
Washington, DC 20528
Dear Secretary Kelly:
The undersigned organizations are greatly concerned that the executive order signed by President Trump on January 27, 2017 will result in discrimination against foreign-born persons from certain predominantly Muslim countries. We are particularly concerned that by restricting entry of physicians and medical students from seven designated Muslim majority countries, the order will undermine medical education and result in patients losing access to their doctors. We are also greatly concerned that the 120 day ban on accepting refugees, and the indefinite ban on Syrian refugees, will contribute to an ongoing public health crisis for those affected, needlessly subjecting them to violence, injury, illness, deprivation and even death. While we are pleased that the courts have temporarily halted implementation of the executive order, the underlying issues of concern about the harm caused by the executive order remain.
The restrictions in the executive order will hinder the free exchange of information and travel among medical students, residents and physicians around the world and result in Americans having poorer access to care. In 2016, 3,769 non-U.S. citizen international medical graduates (IMGs) obtained first-year residency positions. More than half of internal medicine residency positions were filled by IMGs. Approximately 25% of the nation’s physicians are IMGs and provide a disproportionate share of the care to Americans in underserved communities that have a shortage of U.S. born and trained physicians. They also add necessary diversity and cultural competency to our healthcare workforce. If the executive order prevents IMGs from being able to come to the U.S. this could potentially affect the care for thousands of patients.
Our organizations are also especially concerned about refugees with dire medical conditions who had been approved for visas to enter the U.S. but since the executive order, have been unable to enter the country to receive much needed medical care.
While we urge that the executive order be rescinded and replaced with non-discriminatory policies that support families, public health, and medical education, and are pleased that the courts have temporarily halted implementation, there are steps that DHS can take immediately to selectively ease travel restrictions that impact medical education, access to health care services, and public health for individuals who otherwise meet the criteria for immigration, including those from the seven countries identified in the executive order. Specifically, we urge the Department of Homeland Security to:
1. Reinstate the Visa Interview Waiver Program. Suspension of the program “risks creating substantial backlogs in the processing of new and renewal visas for trainees from any foreign
country — delays that create substantial problems for residency programs with trainees on visas and that could interfere with the residency match process this year.”
2. Remove restrictions on entering the U.S. for physicians from the seven designated countries who have been approved for J-1 or H-1B visas and students from those countries with F-1 visas who have been accepted to U.S. medical schools.
3. Develop and implement a plan to allow physicians from the seven designated countries to obtain travel visas to travel to the U.S. for medical conferences and other medical and research-related engagements.
4. Make it a priority to implement a process to admit refugees, without further delay, who had already been vetted and approved for entry prior to the executive order and who are in need of urgent medical care. We note that even with such revisions, the executive order will still inappropriately bar immigrants and refugees based on discriminatory criteria (religion and country of origin) including family members of physicians and medical students in the U.S.
Our organizations are committed to non-discrimination against physicians, medical students and others in immigration policies and offer our assistance in developing policies that support access to health care services, public health, and medical education while balancing the nation’s security needs. Until or unless the executive order is completely rescinded or permanently blocked, it is essential that DHS move forward to ensure that restrictions on physicians and medical students are not reimposed, and that priority is given to refugees with medical conditions needing treatment.
Sincerely,
Alliance for Academic Internal Medicine
American College of Chest Physicians
American College of Physicians
American Society for Gastrointestinal Endoscopy
American Society of Hematology
American Society of Nephrology
American Thoracic Society
Infectious Diseases Society of America
Renal Physicians Association
Society for Adolescent Health and Medicine
Society of Critical Care Medicine
Society of General Internal Medicine
February 7, 2017
The Honorable John F. Kelly
Secretary
U.S. Department of Homeland Security
Washington, DC 20528
Dear Secretary Kelly:
The undersigned organizations are greatly concerned that the executive order signed by President Trump on January 27, 2017 will result in discrimination against foreign-born persons from certain predominantly Muslim countries. We are particularly concerned that by restricting entry of physicians and medical students from seven designated Muslim majority countries, the order will undermine medical education and result in patients losing access to their doctors. We are also greatly concerned that the 120 day ban on accepting refugees, and the indefinite ban on Syrian refugees, will contribute to an ongoing public health crisis for those affected, needlessly subjecting them to violence, injury, illness, deprivation and even death. While we are pleased that the courts have temporarily halted implementation of the executive order, the underlying issues of concern about the harm caused by the executive order remain.
The restrictions in the executive order will hinder the free exchange of information and travel among medical students, residents and physicians around the world and result in Americans having poorer access to care. In 2016, 3,769 non-U.S. citizen international medical graduates (IMGs) obtained first-year residency positions. More than half of internal medicine residency positions were filled by IMGs. Approximately 25% of the nation’s physicians are IMGs and provide a disproportionate share of the care to Americans in underserved communities that have a shortage of U.S. born and trained physicians. They also add necessary diversity and cultural competency to our healthcare workforce. If the executive order prevents IMGs from being able to come to the U.S. this could potentially affect the care for thousands of patients.
Our organizations are also especially concerned about refugees with dire medical conditions who had been approved for visas to enter the U.S. but since the executive order, have been unable to enter the country to receive much needed medical care.
While we urge that the executive order be rescinded and replaced with non-discriminatory policies that support families, public health, and medical education, and are pleased that the courts have temporarily halted implementation, there are steps that DHS can take immediately to selectively ease travel restrictions that impact medical education, access to health care services, and public health for individuals who otherwise meet the criteria for immigration, including those from the seven countries identified in the executive order. Specifically, we urge the Department of Homeland Security to:
1. Reinstate the Visa Interview Waiver Program. Suspension of the program “risks creating substantial backlogs in the processing of new and renewal visas for trainees from any foreign
country — delays that create substantial problems for residency programs with trainees on visas and that could interfere with the residency match process this year.”
2. Remove restrictions on entering the U.S. for physicians from the seven designated countries who have been approved for J-1 or H-1B visas and students from those countries with F-1 visas who have been accepted to U.S. medical schools.
3. Develop and implement a plan to allow physicians from the seven designated countries to obtain travel visas to travel to the U.S. for medical conferences and other medical and research-related engagements.
4. Make it a priority to implement a process to admit refugees, without further delay, who had already been vetted and approved for entry prior to the executive order and who are in need of urgent medical care. We note that even with such revisions, the executive order will still inappropriately bar immigrants and refugees based on discriminatory criteria (religion and country of origin) including family members of physicians and medical students in the U.S.
Our organizations are committed to non-discrimination against physicians, medical students and others in immigration policies and offer our assistance in developing policies that support access to health care services, public health, and medical education while balancing the nation’s security needs. Until or unless the executive order is completely rescinded or permanently blocked, it is essential that DHS move forward to ensure that restrictions on physicians and medical students are not reimposed, and that priority is given to refugees with medical conditions needing treatment.
Sincerely,
Alliance for Academic Internal Medicine
American College of Chest Physicians
American College of Physicians
American Society for Gastrointestinal Endoscopy
American Society of Hematology
American Society of Nephrology
American Thoracic Society
Infectious Diseases Society of America
Renal Physicians Association
Society for Adolescent Health and Medicine
Society of Critical Care Medicine
Society of General Internal Medicine
February 7, 2017
The Honorable John F. Kelly
Secretary
U.S. Department of Homeland Security
Washington, DC 20528
Dear Secretary Kelly:
The undersigned organizations are greatly concerned that the executive order signed by President Trump on January 27, 2017 will result in discrimination against foreign-born persons from certain predominantly Muslim countries. We are particularly concerned that by restricting entry of physicians and medical students from seven designated Muslim majority countries, the order will undermine medical education and result in patients losing access to their doctors. We are also greatly concerned that the 120 day ban on accepting refugees, and the indefinite ban on Syrian refugees, will contribute to an ongoing public health crisis for those affected, needlessly subjecting them to violence, injury, illness, deprivation and even death. While we are pleased that the courts have temporarily halted implementation of the executive order, the underlying issues of concern about the harm caused by the executive order remain.
The restrictions in the executive order will hinder the free exchange of information and travel among medical students, residents and physicians around the world and result in Americans having poorer access to care. In 2016, 3,769 non-U.S. citizen international medical graduates (IMGs) obtained first-year residency positions. More than half of internal medicine residency positions were filled by IMGs. Approximately 25% of the nation’s physicians are IMGs and provide a disproportionate share of the care to Americans in underserved communities that have a shortage of U.S. born and trained physicians. They also add necessary diversity and cultural competency to our healthcare workforce. If the executive order prevents IMGs from being able to come to the U.S. this could potentially affect the care for thousands of patients.
Our organizations are also especially concerned about refugees with dire medical conditions who had been approved for visas to enter the U.S. but since the executive order, have been unable to enter the country to receive much needed medical care.
While we urge that the executive order be rescinded and replaced with non-discriminatory policies that support families, public health, and medical education, and are pleased that the courts have temporarily halted implementation, there are steps that DHS can take immediately to selectively ease travel restrictions that impact medical education, access to health care services, and public health for individuals who otherwise meet the criteria for immigration, including those from the seven countries identified in the executive order. Specifically, we urge the Department of Homeland Security to:
1. Reinstate the Visa Interview Waiver Program. Suspension of the program “risks creating substantial backlogs in the processing of new and renewal visas for trainees from any foreign
country — delays that create substantial problems for residency programs with trainees on visas and that could interfere with the residency match process this year.”
2. Remove restrictions on entering the U.S. for physicians from the seven designated countries who have been approved for J-1 or H-1B visas and students from those countries with F-1 visas who have been accepted to U.S. medical schools.
3. Develop and implement a plan to allow physicians from the seven designated countries to obtain travel visas to travel to the U.S. for medical conferences and other medical and research-related engagements.
4. Make it a priority to implement a process to admit refugees, without further delay, who had already been vetted and approved for entry prior to the executive order and who are in need of urgent medical care. We note that even with such revisions, the executive order will still inappropriately bar immigrants and refugees based on discriminatory criteria (religion and country of origin) including family members of physicians and medical students in the U.S.
Our organizations are committed to non-discrimination against physicians, medical students and others in immigration policies and offer our assistance in developing policies that support access to health care services, public health, and medical education while balancing the nation’s security needs. Until or unless the executive order is completely rescinded or permanently blocked, it is essential that DHS move forward to ensure that restrictions on physicians and medical students are not reimposed, and that priority is given to refugees with medical conditions needing treatment.
Sincerely,
Alliance for Academic Internal Medicine
American College of Chest Physicians
American College of Physicians
American Society for Gastrointestinal Endoscopy
American Society of Hematology
American Society of Nephrology
American Thoracic Society
Infectious Diseases Society of America
Renal Physicians Association
Society for Adolescent Health and Medicine
Society of Critical Care Medicine
Society of General Internal Medicine
President Trump’s revised executive order blocking travelers from six Muslim-majority countries from entering the United States could land a damaging blow to global cooperation in scientific research and could impede assemblies of the world’s top medical experts.
The March 6 executive order bars citizens of Iran, Libya, Somalia, Sudan, Syria, and Yemen from obtaining visas for 90 days and blocks refugees from those countries from entering the United States for 120 days. The measure, which takes effect March 16, supersedes President Trump’s original Jan. 27 travel ban. The new order exempts citizens of the six countries who are legal permanent U.S. residents or who have current visas.
The policy could have detrimental effects on future collaboration between U.S. and international scientists and may ultimately endanger the health and well-being of patients, said International Antiviral Society–U.S.A. executive director and president Donna M. Jacobsen, regarding the original travel ban.
There is “serious reason for concern” that the policy will dissuade scientists and researchers “from traveling to the [United States] in the future overall and sharing their work with colleagues here,” she said.
Thousands of academics from around the world, including physicians, researchers, and professors, have vowed to boycott U.S.-based conferences in light of the Trump administration policy. A Google Docs petition started shortly after the original ban was announced garnered more than 5,000 signatures by professionals acting in solidarity with those affected by the travel restrictions. The academicians who signed the petition said they would not attend international conferences in the United States until those restricted from participating could rejoin their colleagues and freely share their ideas.
The new executive order comes nearly 2 months after President Trump’s original travel ban caused nationwide protests and led to a series of legal challenges. The states of Washington and Minnesota, which sued President Trump over his original ban, argued that such a ban harms the teaching and research missions of their universities and prevents students and faculty from traveling for research and academic collaboration. In addition, the executive order restricts universities from hiring attractive candidates from countries affected by the ban, state officials said. A federal court temporarily blocked the original travel ban on Feb. 3, a decision upheld by the 9th U.S. Circuit Court of Appeals on Feb. 9. The circuit judges said the plaintiffs were likely to succeed in their arguments and that the president had demonstrated no evidence that his executive order advances national security.
The new executive order excludes Iraq and also removes language that had indefinitely banned Syrian refugees. In a March 6 memorandum, the White House said the purpose of the ban is to prevent “foreign nationals who may aid, support, or commit violent, criminal, or terrorist acts,” while the administration enhances the screening and vetting protocols and procedures for granting visas and admission to the United States.
“This nation cannot delay the immediate implementation of additional heightened screening and vetting protocols and procedures for issuing visas to ensure that we strengthen the safety and security of our country,” the memo states.
[email protected]
On Twitter @legal_med
President Trump’s revised executive order blocking travelers from six Muslim-majority countries from entering the United States could land a damaging blow to global cooperation in scientific research and could impede assemblies of the world’s top medical experts.
The March 6 executive order bars citizens of Iran, Libya, Somalia, Sudan, Syria, and Yemen from obtaining visas for 90 days and blocks refugees from those countries from entering the United States for 120 days. The measure, which takes effect March 16, supersedes President Trump’s original Jan. 27 travel ban. The new order exempts citizens of the six countries who are legal permanent U.S. residents or who have current visas.
The policy could have detrimental effects on future collaboration between U.S. and international scientists and may ultimately endanger the health and well-being of patients, said International Antiviral Society–U.S.A. executive director and president Donna M. Jacobsen, regarding the original travel ban.
There is “serious reason for concern” that the policy will dissuade scientists and researchers “from traveling to the [United States] in the future overall and sharing their work with colleagues here,” she said.
Thousands of academics from around the world, including physicians, researchers, and professors, have vowed to boycott U.S.-based conferences in light of the Trump administration policy. A Google Docs petition started shortly after the original ban was announced garnered more than 5,000 signatures by professionals acting in solidarity with those affected by the travel restrictions. The academicians who signed the petition said they would not attend international conferences in the United States until those restricted from participating could rejoin their colleagues and freely share their ideas.
The new executive order comes nearly 2 months after President Trump’s original travel ban caused nationwide protests and led to a series of legal challenges. The states of Washington and Minnesota, which sued President Trump over his original ban, argued that such a ban harms the teaching and research missions of their universities and prevents students and faculty from traveling for research and academic collaboration. In addition, the executive order restricts universities from hiring attractive candidates from countries affected by the ban, state officials said. A federal court temporarily blocked the original travel ban on Feb. 3, a decision upheld by the 9th U.S. Circuit Court of Appeals on Feb. 9. The circuit judges said the plaintiffs were likely to succeed in their arguments and that the president had demonstrated no evidence that his executive order advances national security.
The new executive order excludes Iraq and also removes language that had indefinitely banned Syrian refugees. In a March 6 memorandum, the White House said the purpose of the ban is to prevent “foreign nationals who may aid, support, or commit violent, criminal, or terrorist acts,” while the administration enhances the screening and vetting protocols and procedures for granting visas and admission to the United States.
“This nation cannot delay the immediate implementation of additional heightened screening and vetting protocols and procedures for issuing visas to ensure that we strengthen the safety and security of our country,” the memo states.
[email protected]
On Twitter @legal_med
Methotrexate use justified for early RA, disease prevention
Efforts to delay or prevent rheumatoid arthritis (RA) in individuals at high risk for the disease received a boost from the findings of a subgroup analysis of an older Dutch prevention trial involving methotrexate that were published recently in Arthritis & Rheumatology.
However, while the 22-patient subgroup analysis of the 2007 trial, called PROMPT (Probable RA: Methotrexate Versus Placebo Treatment), showed that 1 year of methotrexate prevented the development of rheumatoid arthritis in significantly more individuals at high risk for the disease than did placebo, hindsight has shown that most of these high-risk individuals actually had RA at baseline as defined by the 2010 American College or Rheumatology/European League Against Rheumatism classification criteria.
Even though the “landscape of RA has changed since this study was conceived, enrolled, and performed,” Dr. Sparks noted that the study provides evidence that today’s “standard of care really works” by making use of data that are unobtainable today.
“Nowadays, we wouldn’t be able to do a placebo-controlled trial in early RA because those patients need to be treated, but at the time, it was perfectly fine, based on the treatment landscape, to put these patients in a [placebo-controlled] trial,” he said in an interview.
“It also demonstrates that you really need to find high-risk individuals, because, if you recruit people who are never going to develop RA, you’re just diluting your effect, and you’re not going to find the difference in the groups based on that diluted effect when there could be a true effect in that special subgroup,” he added.
Senior study author Annette van der Helm-van Mil, MD, PhD, and her colleagues at Leiden (the Netherlands) University Medical Center performed the reanalysis after the initial finding that methotrexate had no preventative effect may have been falsely negative because the study included patients with a low risk of progressing to RA (Arthritis Rheumatol. 2017 Feb 19. doi: 10.1002/art.40062).
In the reanalysis, the investigators defined 22 out of the trial’s 110 participants as high risk based on their score of 8 or higher on the Leiden prediction rule at baseline. Of those 22, 18 also fulfilled the 2010 classification criteria for RA.
This “definition of high risk [in the trial] very much coincided with the new classification criteria and reinforces the standard of care that patients with new diagnosed RA should be treated with DMARDs [disease-modifying antirheumatic drugs] front line,” Dr. Sparks said.
The Leiden prediction rule score is based on ACPA statuses, as well as age, sex, distribution of involved joints, number of swollen and tender joints, severity of morning stiffness, C-reactive protein level, and rheumatoid factor. In previous studies of patients with undifferentiated arthritis, a score of 8 or higher with the prediction rule had a positive predictive value of 84% in patients with undifferentiated arthritis, according to the investigators.
Based on a primary outcome of fulfilling the 1987 classification criteria for RA after 5 years of follow-up, the investigators found that 6 of 11 (55%) in the methotrexate arm developed RA, compared with all 11 patients in the placebo arm (P = .011). “A 1-year course of methotrexate was associated with an absolute risk reduction of 45% on RA development, resulting in a number needed to treat of 2.2 (95% [confidence interval], 1.3-6.2),” the authors wrote.
Furthermore, the time to the development of RA based on the 1987 criteria was longer with methotrexate than with placebo (median of 22.5 months vs. 3 months; P less than .001).
Drug-free remission was also achieved by 4 of 11 (36%) patients taking methotrexate, compared with none of the patients taking placebo (P = .027).
The beneficial effects of methotrexate were seen in ACPA-positive and ACPA-negative high-risk patients but not in patients without a high risk of RA.
For the patients who did not fulfill the 2010 RA criteria at baseline, only one of four of those in the placebo arm did go on to develop RA based on 1987 criteria, whereas only one of three who received methotrexate did.
Overall, the reanalysis of PROMPT trial data illustrates how “noninformative inclusions can blur highly relevant study outcomes, such as prevention of RA,” the study authors concluded.
“As trials are now being conducted to evaluate the efficacy of treatment initiated in the phase of arthralgia, the development of adequate risk prediction models are of importance in order to prevent false-negative study results in the future,” they added.
The PROMPT trial was supported by the Dutch Arthritis Foundation and the Netherlands Organisation for Scientific Research.
Small numbers not withstanding, the findings of this reanalysis of the PROMPT trial are exciting, and they address the importance of identifying the right individuals to include in any type of prevention study in RA.
Given the temporal limits of clinical trials, inclusion criteria will need to incorporate both the likelihood of an important outcome and the timing of that outcome – right individuals, right time, right drug/intervention.
It is hoped that investigators will be able to demonstrate conclusively that preventive interventions work for rheumatic disease once these issues are addressed.
Kevin D. Deane, MD, PhD, and his coauthors are with the division of rheumatology at the University of Colorado, Denver, and made these remarks in an editorial accompanying the PROMPT trial reanalysis (Arthritis Rheumatol. 2017 Feb 19. doi: 10.1002/art.40061).
Small numbers not withstanding, the findings of this reanalysis of the PROMPT trial are exciting, and they address the importance of identifying the right individuals to include in any type of prevention study in RA.
Given the temporal limits of clinical trials, inclusion criteria will need to incorporate both the likelihood of an important outcome and the timing of that outcome – right individuals, right time, right drug/intervention.
It is hoped that investigators will be able to demonstrate conclusively that preventive interventions work for rheumatic disease once these issues are addressed.
Kevin D. Deane, MD, PhD, and his coauthors are with the division of rheumatology at the University of Colorado, Denver, and made these remarks in an editorial accompanying the PROMPT trial reanalysis (Arthritis Rheumatol. 2017 Feb 19. doi: 10.1002/art.40061).
Small numbers not withstanding, the findings of this reanalysis of the PROMPT trial are exciting, and they address the importance of identifying the right individuals to include in any type of prevention study in RA.
Given the temporal limits of clinical trials, inclusion criteria will need to incorporate both the likelihood of an important outcome and the timing of that outcome – right individuals, right time, right drug/intervention.
It is hoped that investigators will be able to demonstrate conclusively that preventive interventions work for rheumatic disease once these issues are addressed.
Kevin D. Deane, MD, PhD, and his coauthors are with the division of rheumatology at the University of Colorado, Denver, and made these remarks in an editorial accompanying the PROMPT trial reanalysis (Arthritis Rheumatol. 2017 Feb 19. doi: 10.1002/art.40061).
Efforts to delay or prevent rheumatoid arthritis (RA) in individuals at high risk for the disease received a boost from the findings of a subgroup analysis of an older Dutch prevention trial involving methotrexate that were published recently in Arthritis & Rheumatology.
However, while the 22-patient subgroup analysis of the 2007 trial, called PROMPT (Probable RA: Methotrexate Versus Placebo Treatment), showed that 1 year of methotrexate prevented the development of rheumatoid arthritis in significantly more individuals at high risk for the disease than did placebo, hindsight has shown that most of these high-risk individuals actually had RA at baseline as defined by the 2010 American College or Rheumatology/European League Against Rheumatism classification criteria.
Even though the “landscape of RA has changed since this study was conceived, enrolled, and performed,” Dr. Sparks noted that the study provides evidence that today’s “standard of care really works” by making use of data that are unobtainable today.
“Nowadays, we wouldn’t be able to do a placebo-controlled trial in early RA because those patients need to be treated, but at the time, it was perfectly fine, based on the treatment landscape, to put these patients in a [placebo-controlled] trial,” he said in an interview.
“It also demonstrates that you really need to find high-risk individuals, because, if you recruit people who are never going to develop RA, you’re just diluting your effect, and you’re not going to find the difference in the groups based on that diluted effect when there could be a true effect in that special subgroup,” he added.
Senior study author Annette van der Helm-van Mil, MD, PhD, and her colleagues at Leiden (the Netherlands) University Medical Center performed the reanalysis after the initial finding that methotrexate had no preventative effect may have been falsely negative because the study included patients with a low risk of progressing to RA (Arthritis Rheumatol. 2017 Feb 19. doi: 10.1002/art.40062).
In the reanalysis, the investigators defined 22 out of the trial’s 110 participants as high risk based on their score of 8 or higher on the Leiden prediction rule at baseline. Of those 22, 18 also fulfilled the 2010 classification criteria for RA.
This “definition of high risk [in the trial] very much coincided with the new classification criteria and reinforces the standard of care that patients with new diagnosed RA should be treated with DMARDs [disease-modifying antirheumatic drugs] front line,” Dr. Sparks said.
The Leiden prediction rule score is based on ACPA statuses, as well as age, sex, distribution of involved joints, number of swollen and tender joints, severity of morning stiffness, C-reactive protein level, and rheumatoid factor. In previous studies of patients with undifferentiated arthritis, a score of 8 or higher with the prediction rule had a positive predictive value of 84% in patients with undifferentiated arthritis, according to the investigators.
Based on a primary outcome of fulfilling the 1987 classification criteria for RA after 5 years of follow-up, the investigators found that 6 of 11 (55%) in the methotrexate arm developed RA, compared with all 11 patients in the placebo arm (P = .011). “A 1-year course of methotrexate was associated with an absolute risk reduction of 45% on RA development, resulting in a number needed to treat of 2.2 (95% [confidence interval], 1.3-6.2),” the authors wrote.
Furthermore, the time to the development of RA based on the 1987 criteria was longer with methotrexate than with placebo (median of 22.5 months vs. 3 months; P less than .001).
Drug-free remission was also achieved by 4 of 11 (36%) patients taking methotrexate, compared with none of the patients taking placebo (P = .027).
The beneficial effects of methotrexate were seen in ACPA-positive and ACPA-negative high-risk patients but not in patients without a high risk of RA.
For the patients who did not fulfill the 2010 RA criteria at baseline, only one of four of those in the placebo arm did go on to develop RA based on 1987 criteria, whereas only one of three who received methotrexate did.
Overall, the reanalysis of PROMPT trial data illustrates how “noninformative inclusions can blur highly relevant study outcomes, such as prevention of RA,” the study authors concluded.
“As trials are now being conducted to evaluate the efficacy of treatment initiated in the phase of arthralgia, the development of adequate risk prediction models are of importance in order to prevent false-negative study results in the future,” they added.
The PROMPT trial was supported by the Dutch Arthritis Foundation and the Netherlands Organisation for Scientific Research.
Efforts to delay or prevent rheumatoid arthritis (RA) in individuals at high risk for the disease received a boost from the findings of a subgroup analysis of an older Dutch prevention trial involving methotrexate that were published recently in Arthritis & Rheumatology.
However, while the 22-patient subgroup analysis of the 2007 trial, called PROMPT (Probable RA: Methotrexate Versus Placebo Treatment), showed that 1 year of methotrexate prevented the development of rheumatoid arthritis in significantly more individuals at high risk for the disease than did placebo, hindsight has shown that most of these high-risk individuals actually had RA at baseline as defined by the 2010 American College or Rheumatology/European League Against Rheumatism classification criteria.
Even though the “landscape of RA has changed since this study was conceived, enrolled, and performed,” Dr. Sparks noted that the study provides evidence that today’s “standard of care really works” by making use of data that are unobtainable today.
“Nowadays, we wouldn’t be able to do a placebo-controlled trial in early RA because those patients need to be treated, but at the time, it was perfectly fine, based on the treatment landscape, to put these patients in a [placebo-controlled] trial,” he said in an interview.
“It also demonstrates that you really need to find high-risk individuals, because, if you recruit people who are never going to develop RA, you’re just diluting your effect, and you’re not going to find the difference in the groups based on that diluted effect when there could be a true effect in that special subgroup,” he added.
Senior study author Annette van der Helm-van Mil, MD, PhD, and her colleagues at Leiden (the Netherlands) University Medical Center performed the reanalysis after the initial finding that methotrexate had no preventative effect may have been falsely negative because the study included patients with a low risk of progressing to RA (Arthritis Rheumatol. 2017 Feb 19. doi: 10.1002/art.40062).
In the reanalysis, the investigators defined 22 out of the trial’s 110 participants as high risk based on their score of 8 or higher on the Leiden prediction rule at baseline. Of those 22, 18 also fulfilled the 2010 classification criteria for RA.
This “definition of high risk [in the trial] very much coincided with the new classification criteria and reinforces the standard of care that patients with new diagnosed RA should be treated with DMARDs [disease-modifying antirheumatic drugs] front line,” Dr. Sparks said.
The Leiden prediction rule score is based on ACPA statuses, as well as age, sex, distribution of involved joints, number of swollen and tender joints, severity of morning stiffness, C-reactive protein level, and rheumatoid factor. In previous studies of patients with undifferentiated arthritis, a score of 8 or higher with the prediction rule had a positive predictive value of 84% in patients with undifferentiated arthritis, according to the investigators.
Based on a primary outcome of fulfilling the 1987 classification criteria for RA after 5 years of follow-up, the investigators found that 6 of 11 (55%) in the methotrexate arm developed RA, compared with all 11 patients in the placebo arm (P = .011). “A 1-year course of methotrexate was associated with an absolute risk reduction of 45% on RA development, resulting in a number needed to treat of 2.2 (95% [confidence interval], 1.3-6.2),” the authors wrote.
Furthermore, the time to the development of RA based on the 1987 criteria was longer with methotrexate than with placebo (median of 22.5 months vs. 3 months; P less than .001).
Drug-free remission was also achieved by 4 of 11 (36%) patients taking methotrexate, compared with none of the patients taking placebo (P = .027).
The beneficial effects of methotrexate were seen in ACPA-positive and ACPA-negative high-risk patients but not in patients without a high risk of RA.
For the patients who did not fulfill the 2010 RA criteria at baseline, only one of four of those in the placebo arm did go on to develop RA based on 1987 criteria, whereas only one of three who received methotrexate did.
Overall, the reanalysis of PROMPT trial data illustrates how “noninformative inclusions can blur highly relevant study outcomes, such as prevention of RA,” the study authors concluded.
“As trials are now being conducted to evaluate the efficacy of treatment initiated in the phase of arthralgia, the development of adequate risk prediction models are of importance in order to prevent false-negative study results in the future,” they added.
The PROMPT trial was supported by the Dutch Arthritis Foundation and the Netherlands Organisation for Scientific Research.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point:
Main finding: In people deemed to be at high risk for RA, a 1-year course of methotrexate was associated with an absolute risk reduction of 45% of RA development, resulting in a number needed to treat of 2.2 (95% CI, 1.3-6.2).
Data source: A reanalysis of the PROMPT trial involving 110 patients with undifferentiated arthritis randomized to a 1-year course of methotrexate or placebo.
Disclosures: The PROMPT trial was supported by the Dutch Arthritis Foundation and the Netherlands Organisation for Scientific Research.