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Adalimumab biosimilar Cyltezo gets interchangeability designation
The Food and Drug Administration approved a supplement to the biologics license application of the adalimumab biosimilar drug Cyltezo (adalimumab-adbm) that makes it the first interchangeable biosimilar with Humira (adalimumab), the original branded version of the drug, its manufacturer Boehringer Ingelheim announced Oct. 15.
The FDA originally approved Cyltezo in 2017 for the treatment of multiple chronic inflammatory diseases, including seven of Humira’s nine indications for adults and pediatric patients: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis.
The interchangeability designation means that Cyltezo was tested in an additional clinical trial in which patients were successfully switched back and forth multiple times from Humira to Cyltezo and allows pharmacists to autosubstitute Humira with Cyltezo. In these cases, individual state laws control how and whether physicians will be notified of this switch.
Cyltezo is just the second biosimilar to be designated as interchangeable with its originator biologic product. The first approval, announced July 28, was for the interchangeability of Semglee (insulin glargine-yfgn) with the originator Lantus.
The agency based its decision on positive data from the VOLTAIRE-X study of 238 patients with moderate to severe chronic plaque psoriasis in which Cyltezo had no meaningful clinical differences from Humira in pharmacokinetics, efficacy, immunogenicity, and safety between the switching and continuous treatment groups.
Cyltezo will not be commercially available in the United States until July 1, 2023, according to Boehringer Ingelheim.
The Food and Drug Administration approved a supplement to the biologics license application of the adalimumab biosimilar drug Cyltezo (adalimumab-adbm) that makes it the first interchangeable biosimilar with Humira (adalimumab), the original branded version of the drug, its manufacturer Boehringer Ingelheim announced Oct. 15.
The FDA originally approved Cyltezo in 2017 for the treatment of multiple chronic inflammatory diseases, including seven of Humira’s nine indications for adults and pediatric patients: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis.
The interchangeability designation means that Cyltezo was tested in an additional clinical trial in which patients were successfully switched back and forth multiple times from Humira to Cyltezo and allows pharmacists to autosubstitute Humira with Cyltezo. In these cases, individual state laws control how and whether physicians will be notified of this switch.
Cyltezo is just the second biosimilar to be designated as interchangeable with its originator biologic product. The first approval, announced July 28, was for the interchangeability of Semglee (insulin glargine-yfgn) with the originator Lantus.
The agency based its decision on positive data from the VOLTAIRE-X study of 238 patients with moderate to severe chronic plaque psoriasis in which Cyltezo had no meaningful clinical differences from Humira in pharmacokinetics, efficacy, immunogenicity, and safety between the switching and continuous treatment groups.
Cyltezo will not be commercially available in the United States until July 1, 2023, according to Boehringer Ingelheim.
The Food and Drug Administration approved a supplement to the biologics license application of the adalimumab biosimilar drug Cyltezo (adalimumab-adbm) that makes it the first interchangeable biosimilar with Humira (adalimumab), the original branded version of the drug, its manufacturer Boehringer Ingelheim announced Oct. 15.
The FDA originally approved Cyltezo in 2017 for the treatment of multiple chronic inflammatory diseases, including seven of Humira’s nine indications for adults and pediatric patients: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis.
The interchangeability designation means that Cyltezo was tested in an additional clinical trial in which patients were successfully switched back and forth multiple times from Humira to Cyltezo and allows pharmacists to autosubstitute Humira with Cyltezo. In these cases, individual state laws control how and whether physicians will be notified of this switch.
Cyltezo is just the second biosimilar to be designated as interchangeable with its originator biologic product. The first approval, announced July 28, was for the interchangeability of Semglee (insulin glargine-yfgn) with the originator Lantus.
The agency based its decision on positive data from the VOLTAIRE-X study of 238 patients with moderate to severe chronic plaque psoriasis in which Cyltezo had no meaningful clinical differences from Humira in pharmacokinetics, efficacy, immunogenicity, and safety between the switching and continuous treatment groups.
Cyltezo will not be commercially available in the United States until July 1, 2023, according to Boehringer Ingelheim.
European agency supports marketing of abrocitinib for atopic dermatitis
The
The full indication is for the treatment of moderate to severe AD in adults who are candidates for systemic therapy, according to a summary of the opinion, made on Oct. 14. It will be available as 50-mg, 100-mg, and 200-mg tablets, will be marketed under the name Cibinqo, and “should be prescribed by physicians experienced in the treatment of atopic dermatitis,” the statement said.
“The benefits of Cibinqo are its ability to improve the skin condition as measured by improvements in the Investigator’s Global Assessment 0/1 and Eczema Area and Severity Index 75 response and to reduce itching in patients with atopic dermatitis,” according to the opinion. The most common side effects of abrocitinib are nausea, headache, acne, herpes simplex, increased blood creatine phosphokinase, vomiting, dizziness, and upper abdominal pain, the statement said, and infections are the most serious.
Abrocitinib was first approved for AD in the United Kingdom and in Japan in September, and is under review at the Food and Drug Administration for this indication. The first JAK inhibitor approved for AD in the United States is topical ruxolitinib (Opzelura), approved in September, for the short-term, noncontinuous chronic treatment of mild to moderate AD in nonimmunocompromised patients aged 12 years and older whose disease is not adequately controlled with topical prescription treatments, “or when those therapies are not advisable.”
The
The full indication is for the treatment of moderate to severe AD in adults who are candidates for systemic therapy, according to a summary of the opinion, made on Oct. 14. It will be available as 50-mg, 100-mg, and 200-mg tablets, will be marketed under the name Cibinqo, and “should be prescribed by physicians experienced in the treatment of atopic dermatitis,” the statement said.
“The benefits of Cibinqo are its ability to improve the skin condition as measured by improvements in the Investigator’s Global Assessment 0/1 and Eczema Area and Severity Index 75 response and to reduce itching in patients with atopic dermatitis,” according to the opinion. The most common side effects of abrocitinib are nausea, headache, acne, herpes simplex, increased blood creatine phosphokinase, vomiting, dizziness, and upper abdominal pain, the statement said, and infections are the most serious.
Abrocitinib was first approved for AD in the United Kingdom and in Japan in September, and is under review at the Food and Drug Administration for this indication. The first JAK inhibitor approved for AD in the United States is topical ruxolitinib (Opzelura), approved in September, for the short-term, noncontinuous chronic treatment of mild to moderate AD in nonimmunocompromised patients aged 12 years and older whose disease is not adequately controlled with topical prescription treatments, “or when those therapies are not advisable.”
The
The full indication is for the treatment of moderate to severe AD in adults who are candidates for systemic therapy, according to a summary of the opinion, made on Oct. 14. It will be available as 50-mg, 100-mg, and 200-mg tablets, will be marketed under the name Cibinqo, and “should be prescribed by physicians experienced in the treatment of atopic dermatitis,” the statement said.
“The benefits of Cibinqo are its ability to improve the skin condition as measured by improvements in the Investigator’s Global Assessment 0/1 and Eczema Area and Severity Index 75 response and to reduce itching in patients with atopic dermatitis,” according to the opinion. The most common side effects of abrocitinib are nausea, headache, acne, herpes simplex, increased blood creatine phosphokinase, vomiting, dizziness, and upper abdominal pain, the statement said, and infections are the most serious.
Abrocitinib was first approved for AD in the United Kingdom and in Japan in September, and is under review at the Food and Drug Administration for this indication. The first JAK inhibitor approved for AD in the United States is topical ruxolitinib (Opzelura), approved in September, for the short-term, noncontinuous chronic treatment of mild to moderate AD in nonimmunocompromised patients aged 12 years and older whose disease is not adequately controlled with topical prescription treatments, “or when those therapies are not advisable.”
Itchy vesicles
The patient’s history of celiac disease and the presence of vesicular lesions affecting primarily extensor surfaces pointed to a diagnosis of dermatitis herpetiformis (DH).
DH is an autoimmune skin condition that is associated with gluten sensitivity. It is more frequent in individuals of northern European heritage.1
The lesions associated with DH are intensely pruritic grouped papules, vesicles, and tense blisters that appear more commonly on extensor areas of the lower limbs, elbows, buttocks, and sacral region. Involvement of the oral mucosa is rare and not all patients with DH experience the intestinal symptoms of gluten sensitivity.
Direct immunofluorescence of perilesional skin is the gold standard to confirm the diagnosis. Histology of the lesions is also performed, but findings may vary depending on the age of the lesion. Additionally, serology can help to confirm the diagnosis. Both tissue and epidermal transglutaminase antibodies are often present in the serum but may be negative if the patient is following a gluten-free diet. In this case, biopsy was not ordered because the patient already had a biopsy-confirmed diagnosis of celiac disease and a classic presentation of lesions.
Treatment of DH consists of a strict gluten-free diet and dapsone as first-line pharmacologic therapy. Typically, dapsone is started at doses of 25 to 50 mg daily and increased, as needed and tolerated, to 100 to 200 mg per day. Improvement is usually seen within 2 days of treatment initiation. Dapsone has multiple potential adverse effects; the most common is hemolysis. Since individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency can develop severe hemolysis if treated with dapsone, it is necessary to screen for this condition prior to initiation of treatment. A complete blood count and liver and renal function testing are typically done before, and during, treatment with dapsone.1
This patient had normal levels of G6PD and his screening labs were also normal. He was started on dapsone orally 25 mg/d and follow-up was pending.
Image courtesy of Daniel Stulberg, MD. Text courtesy of Marcella Colom, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.
1. Mendes FBR, Hissa-Elian A, de Abreu MAMM, et al. Review: dermatitis herpetiformis. An Bras Dermatol. 2013;88:594-599. doi:10.1590/abd1806-4841.20131775
The patient’s history of celiac disease and the presence of vesicular lesions affecting primarily extensor surfaces pointed to a diagnosis of dermatitis herpetiformis (DH).
DH is an autoimmune skin condition that is associated with gluten sensitivity. It is more frequent in individuals of northern European heritage.1
The lesions associated with DH are intensely pruritic grouped papules, vesicles, and tense blisters that appear more commonly on extensor areas of the lower limbs, elbows, buttocks, and sacral region. Involvement of the oral mucosa is rare and not all patients with DH experience the intestinal symptoms of gluten sensitivity.
Direct immunofluorescence of perilesional skin is the gold standard to confirm the diagnosis. Histology of the lesions is also performed, but findings may vary depending on the age of the lesion. Additionally, serology can help to confirm the diagnosis. Both tissue and epidermal transglutaminase antibodies are often present in the serum but may be negative if the patient is following a gluten-free diet. In this case, biopsy was not ordered because the patient already had a biopsy-confirmed diagnosis of celiac disease and a classic presentation of lesions.
Treatment of DH consists of a strict gluten-free diet and dapsone as first-line pharmacologic therapy. Typically, dapsone is started at doses of 25 to 50 mg daily and increased, as needed and tolerated, to 100 to 200 mg per day. Improvement is usually seen within 2 days of treatment initiation. Dapsone has multiple potential adverse effects; the most common is hemolysis. Since individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency can develop severe hemolysis if treated with dapsone, it is necessary to screen for this condition prior to initiation of treatment. A complete blood count and liver and renal function testing are typically done before, and during, treatment with dapsone.1
This patient had normal levels of G6PD and his screening labs were also normal. He was started on dapsone orally 25 mg/d and follow-up was pending.
Image courtesy of Daniel Stulberg, MD. Text courtesy of Marcella Colom, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.
The patient’s history of celiac disease and the presence of vesicular lesions affecting primarily extensor surfaces pointed to a diagnosis of dermatitis herpetiformis (DH).
DH is an autoimmune skin condition that is associated with gluten sensitivity. It is more frequent in individuals of northern European heritage.1
The lesions associated with DH are intensely pruritic grouped papules, vesicles, and tense blisters that appear more commonly on extensor areas of the lower limbs, elbows, buttocks, and sacral region. Involvement of the oral mucosa is rare and not all patients with DH experience the intestinal symptoms of gluten sensitivity.
Direct immunofluorescence of perilesional skin is the gold standard to confirm the diagnosis. Histology of the lesions is also performed, but findings may vary depending on the age of the lesion. Additionally, serology can help to confirm the diagnosis. Both tissue and epidermal transglutaminase antibodies are often present in the serum but may be negative if the patient is following a gluten-free diet. In this case, biopsy was not ordered because the patient already had a biopsy-confirmed diagnosis of celiac disease and a classic presentation of lesions.
Treatment of DH consists of a strict gluten-free diet and dapsone as first-line pharmacologic therapy. Typically, dapsone is started at doses of 25 to 50 mg daily and increased, as needed and tolerated, to 100 to 200 mg per day. Improvement is usually seen within 2 days of treatment initiation. Dapsone has multiple potential adverse effects; the most common is hemolysis. Since individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency can develop severe hemolysis if treated with dapsone, it is necessary to screen for this condition prior to initiation of treatment. A complete blood count and liver and renal function testing are typically done before, and during, treatment with dapsone.1
This patient had normal levels of G6PD and his screening labs were also normal. He was started on dapsone orally 25 mg/d and follow-up was pending.
Image courtesy of Daniel Stulberg, MD. Text courtesy of Marcella Colom, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.
1. Mendes FBR, Hissa-Elian A, de Abreu MAMM, et al. Review: dermatitis herpetiformis. An Bras Dermatol. 2013;88:594-599. doi:10.1590/abd1806-4841.20131775
1. Mendes FBR, Hissa-Elian A, de Abreu MAMM, et al. Review: dermatitis herpetiformis. An Bras Dermatol. 2013;88:594-599. doi:10.1590/abd1806-4841.20131775
Fecal microbiota transplants may improve resistance to melanoma immunotherapy
In the fall of 2020, Hassane M. Zarour, MD, and colleagues began to pore over raw data from their
Preclinical mouse studies have demonstrated that the gut microbiota could influence the response of tumors to anti–PD-1 immunotherapy, but FMT had not been previously evaluated in human patients with malignant melanoma whose disease persisted or progressed after medical therapy. Only 30%-40% of melanoma patients respond to anti–PD-1 immunotherapy, so the researchers’ sense of anticipation was palpable. “It’s a high-risk, high-reward study, so you never know,” Dr. Zarour, a dermatologist and immunologist who is coleader of the melanoma program at the University of Pittsburgh Medical Center’s Hillman Cancer Center, said in an interview.
For the study, which was funded by the National Institutes of Health and published in Science, Dr. Zarour and a team of colleagues, including Diwakar Davar, MD, a medical oncologist/hematologist at UPMC and Giorgio Trinchieri, MD, head of the cancer immunology section at the National Cancer Institute, enrolled 16 patients with advanced melanoma whose disease had persisted or progressed with anti-PD-1 drugs; donors were 7 patients with advanced melanoma who had responded to pembrolizumab, 4 with a complete response and 3 with a partial response, with a median progression-free survival of 56 months.
After donors and patients underwent serial stool sampling and studies to stamp out the potential for transmitting infectious agents, the researchers administered the donor-derived FMT to patients via colonoscopy every 14 days for 3 weeks, followed by pembrolizumab. To their delight, 6 of the 15 evaluable recipients responded to treatment, with a reduction in tumor or long-term disease stabilization. Moreover, responders also showed increased abundance of taxa that were previously associated with response to immunotherapy, increased activation of CD8+ T cells, and decreased frequency of interleukin-8–expressing myeloid cells.
“This opens new doors for the future,” Dr. Zarour said. “It’s very encouraging, but I don’t want to overstate the data. It’s a small, nonrandomized trial, but one has to keep in mind that people were skeptical about this work; they didn’t think FMT would work. Now we see many people coming into the field to investigate the role of the microbiome as a therapeutic tool, which is great.”
Teri Greiling, MD, characterized the finding as a key development in understanding the microbiome’s potential to influence the course of melanoma and other diseases. “What’s emerging over the last decade of research is that our immune system has a close, back-and-forth relationship with our microbiota,” said Dr. Greiling, associate professor of dermatology at Oregon Health & Science University, Portland. “From day 1 of birth, we’re colonized by microbes that train our immune system how to function. In response, your immune system keeps those microbes in check and shapes which ones are allowed to colonize, and which ones are a target for attack. Thus, inflammatory responses are generated. Similarly, the goal of immunotherapy is to activate the immune system to fight cancer. This study shows that the immune system continues to need the colonizing microbes in our body to function optimally.”
Immunotherapy with checkpoint inhibitors was not an option for malignant melanoma patients until 2011, she noted, so the potential for FMT to further improve outcomes is welcome news for patients and their families. “We went from a less than 5% chance of survival with metastatic melanoma to now, with the right combination of checkpoint inhibitors, we’re up over 50%, which is amazing in a decade,” Dr. Greiling said. “Still, we’re losing half of our patients. If [FMT provides] a 30% improvement over that, that would be great, but it’s hard to extrapolate from such small numbers.”
Positive results in an Israeli study
Results from a similar, smaller phase 1 trial of 2 FMT donors and 10 recipients with metastatic melanoma who had progressed on anti-PD-1 therapy, from the Ella Lemelbaum Institute for Immuno-Oncology at Sheba Medical Center in Tel HaShomer, Israel, yielded similar results. The FMT protocol in this study included colonoscopy and oral stool capsules, followed by the reintroduction of anti–PD-1 therapy with nivolumab. The two FMT donors had previously been treated with anti–PD-1 monotherapy for metastatic melanoma and had achieved a clinical response for at least 1 year. Of the 10 FMT recipients, 1 had a complete response and 2 had a partial response.
“We expected changes in the immune system but did not expect that 3 out of the 10 patients in our study would be turned from nonresponders to responders,” the study’s lead author, Erez N. Baruch, MD, PhD, told this news organization. “Since this was a first-in-human study, we were aiming to assess safety and not clinical responses. [We found] that microbiota modulation can change the immune infiltration within melanoma tumors and by this affect response to immunotherapy.”
Dr. Baruch, an internal medicine resident in the physician-scientist track program at the University of Texas, Houston, said that the findings create a potential new therapeutic paradigm, or a new “playing ground” for drug development that can support existing immunotherapies. “It is important for dermatologists to understand that disruptions of the gut microbiota, mainly by antibiotics, may be harmful to melanoma patients,” he said. “Antibiotics in cancer patients should be used judiciously but of course should not be avoided when there’s an indication.”
As for next steps, Dr. Zarour and colleagues are recruiting more patients to boost their sample size and conducting sequential analysis of the microbiome of study participants “to better determine what the good and bad bugs are,” he said. “There are so many variables, including diet and geography. We need more data.” The hope is to develop a “microbiome signature” to identify patients likely to respond to FMT, and maybe one day, a probiotic capsule that patients take to optimize their response to immunotherapy.
“We don’t want to say that the microbiome is responsible for everything, but it’s responsible for some of the response and some of the resistance to treatment,” Dr. Zarour said. “So, we want to identify what candidate nonresponders are more likely to respond to FMT and be able to stick the right stool in the donor. This goes to better education of the microbiome signature. We are working hard on that.”
Dr. Baruch added that performing FMT for melanoma patients requires tight collaborations between oncologists, dermatologists, GI, and infectious disease experts. “These usually can be done in the setting of large cancer centers and will probably not be available in any hospital,” he said. “This is why understanding the mechanisms and developing an FMT-like drug is important. We are focusing on studying the mechanisms behind the clinical effect in order to develop a drug with an FMT-like effect without the safety and logistic issues related to FMTs.”
Tamia A. Harris-Tryon, MD, PhD, whose lab at the University of Texas Southwestern Medical Center at Dallas is studying how diet and the microbiota impact skin immunity, underscored the importance of evaluating the characteristics of the diet of patients as trials of FMT in melanoma patients carry on. “We know that the diet impacts the repertoire of microbes that colonize the gut,” said Dr. Harris-Tryon, assistant professor in the department of dermatology at the medical center. “The diet of the recipient likely has an impact” on the success of donor FMT.
She also noted that other skin conditions have been linked to a disrupted gut microbiome, such as psoriasis. “Given the safety of FMT in both of these studies, trials of FMT in psoriasis and other systemic skin conditions should be considered,” she said.
According to Dr. Zarour, mounting data from separate studies show that some gut microbiota play a role in adverse events experienced by melanoma patients on immunotherapy. “That is very important, especially with combination therapy,” he said. “There are also microbes involved in resistance to treatment, so the idea would be to identify these microbes.”
Studies raise more questions
In the opinion of Dr. Greiling, results from these two studies raise more questions than they answer. “The big question ... is why and how does FMT work, and how can we make the response better?” she said. “Is there one particular gene product from one microbe that is the key magic ingredient, and we can harness this as a drug? More likely it’s a complex interplay between multiple bacterial species needed to direct the immune response. Is there a group of microbes that is the same from person to person, or is it more complex?”
Then there are pending regulatory concerns. “We know that FMT works for [Clostridioides] difficile colitis but it’s not officially [Food and Drug Administration] approved,” Dr. Greiling said. “The FDA is really struggling with how to approve or regulate using bacteria as a drug. Where is that crossover? That inhibits things moving forward, for good reason. You want to balance safety with live microbes.”
The UPMC clinical trial was supported by Merck. Dr. Zarour disclosed that he is supported by grants from the National Cancer Institute and the James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research at UPMC. The Israeli study was funded by the Ella Lemelbaum Institute for Immuno-Oncology. Dr. Baruch was supported by the Allen Berg Fund for Excellence in Immuno-Oncology Research. Dr. Greiling and Dr. Harris-Tryon reported having no relevant financial disclosures.
In the fall of 2020, Hassane M. Zarour, MD, and colleagues began to pore over raw data from their
Preclinical mouse studies have demonstrated that the gut microbiota could influence the response of tumors to anti–PD-1 immunotherapy, but FMT had not been previously evaluated in human patients with malignant melanoma whose disease persisted or progressed after medical therapy. Only 30%-40% of melanoma patients respond to anti–PD-1 immunotherapy, so the researchers’ sense of anticipation was palpable. “It’s a high-risk, high-reward study, so you never know,” Dr. Zarour, a dermatologist and immunologist who is coleader of the melanoma program at the University of Pittsburgh Medical Center’s Hillman Cancer Center, said in an interview.
For the study, which was funded by the National Institutes of Health and published in Science, Dr. Zarour and a team of colleagues, including Diwakar Davar, MD, a medical oncologist/hematologist at UPMC and Giorgio Trinchieri, MD, head of the cancer immunology section at the National Cancer Institute, enrolled 16 patients with advanced melanoma whose disease had persisted or progressed with anti-PD-1 drugs; donors were 7 patients with advanced melanoma who had responded to pembrolizumab, 4 with a complete response and 3 with a partial response, with a median progression-free survival of 56 months.
After donors and patients underwent serial stool sampling and studies to stamp out the potential for transmitting infectious agents, the researchers administered the donor-derived FMT to patients via colonoscopy every 14 days for 3 weeks, followed by pembrolizumab. To their delight, 6 of the 15 evaluable recipients responded to treatment, with a reduction in tumor or long-term disease stabilization. Moreover, responders also showed increased abundance of taxa that were previously associated with response to immunotherapy, increased activation of CD8+ T cells, and decreased frequency of interleukin-8–expressing myeloid cells.
“This opens new doors for the future,” Dr. Zarour said. “It’s very encouraging, but I don’t want to overstate the data. It’s a small, nonrandomized trial, but one has to keep in mind that people were skeptical about this work; they didn’t think FMT would work. Now we see many people coming into the field to investigate the role of the microbiome as a therapeutic tool, which is great.”
Teri Greiling, MD, characterized the finding as a key development in understanding the microbiome’s potential to influence the course of melanoma and other diseases. “What’s emerging over the last decade of research is that our immune system has a close, back-and-forth relationship with our microbiota,” said Dr. Greiling, associate professor of dermatology at Oregon Health & Science University, Portland. “From day 1 of birth, we’re colonized by microbes that train our immune system how to function. In response, your immune system keeps those microbes in check and shapes which ones are allowed to colonize, and which ones are a target for attack. Thus, inflammatory responses are generated. Similarly, the goal of immunotherapy is to activate the immune system to fight cancer. This study shows that the immune system continues to need the colonizing microbes in our body to function optimally.”
Immunotherapy with checkpoint inhibitors was not an option for malignant melanoma patients until 2011, she noted, so the potential for FMT to further improve outcomes is welcome news for patients and their families. “We went from a less than 5% chance of survival with metastatic melanoma to now, with the right combination of checkpoint inhibitors, we’re up over 50%, which is amazing in a decade,” Dr. Greiling said. “Still, we’re losing half of our patients. If [FMT provides] a 30% improvement over that, that would be great, but it’s hard to extrapolate from such small numbers.”
Positive results in an Israeli study
Results from a similar, smaller phase 1 trial of 2 FMT donors and 10 recipients with metastatic melanoma who had progressed on anti-PD-1 therapy, from the Ella Lemelbaum Institute for Immuno-Oncology at Sheba Medical Center in Tel HaShomer, Israel, yielded similar results. The FMT protocol in this study included colonoscopy and oral stool capsules, followed by the reintroduction of anti–PD-1 therapy with nivolumab. The two FMT donors had previously been treated with anti–PD-1 monotherapy for metastatic melanoma and had achieved a clinical response for at least 1 year. Of the 10 FMT recipients, 1 had a complete response and 2 had a partial response.
“We expected changes in the immune system but did not expect that 3 out of the 10 patients in our study would be turned from nonresponders to responders,” the study’s lead author, Erez N. Baruch, MD, PhD, told this news organization. “Since this was a first-in-human study, we were aiming to assess safety and not clinical responses. [We found] that microbiota modulation can change the immune infiltration within melanoma tumors and by this affect response to immunotherapy.”
Dr. Baruch, an internal medicine resident in the physician-scientist track program at the University of Texas, Houston, said that the findings create a potential new therapeutic paradigm, or a new “playing ground” for drug development that can support existing immunotherapies. “It is important for dermatologists to understand that disruptions of the gut microbiota, mainly by antibiotics, may be harmful to melanoma patients,” he said. “Antibiotics in cancer patients should be used judiciously but of course should not be avoided when there’s an indication.”
As for next steps, Dr. Zarour and colleagues are recruiting more patients to boost their sample size and conducting sequential analysis of the microbiome of study participants “to better determine what the good and bad bugs are,” he said. “There are so many variables, including diet and geography. We need more data.” The hope is to develop a “microbiome signature” to identify patients likely to respond to FMT, and maybe one day, a probiotic capsule that patients take to optimize their response to immunotherapy.
“We don’t want to say that the microbiome is responsible for everything, but it’s responsible for some of the response and some of the resistance to treatment,” Dr. Zarour said. “So, we want to identify what candidate nonresponders are more likely to respond to FMT and be able to stick the right stool in the donor. This goes to better education of the microbiome signature. We are working hard on that.”
Dr. Baruch added that performing FMT for melanoma patients requires tight collaborations between oncologists, dermatologists, GI, and infectious disease experts. “These usually can be done in the setting of large cancer centers and will probably not be available in any hospital,” he said. “This is why understanding the mechanisms and developing an FMT-like drug is important. We are focusing on studying the mechanisms behind the clinical effect in order to develop a drug with an FMT-like effect without the safety and logistic issues related to FMTs.”
Tamia A. Harris-Tryon, MD, PhD, whose lab at the University of Texas Southwestern Medical Center at Dallas is studying how diet and the microbiota impact skin immunity, underscored the importance of evaluating the characteristics of the diet of patients as trials of FMT in melanoma patients carry on. “We know that the diet impacts the repertoire of microbes that colonize the gut,” said Dr. Harris-Tryon, assistant professor in the department of dermatology at the medical center. “The diet of the recipient likely has an impact” on the success of donor FMT.
She also noted that other skin conditions have been linked to a disrupted gut microbiome, such as psoriasis. “Given the safety of FMT in both of these studies, trials of FMT in psoriasis and other systemic skin conditions should be considered,” she said.
According to Dr. Zarour, mounting data from separate studies show that some gut microbiota play a role in adverse events experienced by melanoma patients on immunotherapy. “That is very important, especially with combination therapy,” he said. “There are also microbes involved in resistance to treatment, so the idea would be to identify these microbes.”
Studies raise more questions
In the opinion of Dr. Greiling, results from these two studies raise more questions than they answer. “The big question ... is why and how does FMT work, and how can we make the response better?” she said. “Is there one particular gene product from one microbe that is the key magic ingredient, and we can harness this as a drug? More likely it’s a complex interplay between multiple bacterial species needed to direct the immune response. Is there a group of microbes that is the same from person to person, or is it more complex?”
Then there are pending regulatory concerns. “We know that FMT works for [Clostridioides] difficile colitis but it’s not officially [Food and Drug Administration] approved,” Dr. Greiling said. “The FDA is really struggling with how to approve or regulate using bacteria as a drug. Where is that crossover? That inhibits things moving forward, for good reason. You want to balance safety with live microbes.”
The UPMC clinical trial was supported by Merck. Dr. Zarour disclosed that he is supported by grants from the National Cancer Institute and the James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research at UPMC. The Israeli study was funded by the Ella Lemelbaum Institute for Immuno-Oncology. Dr. Baruch was supported by the Allen Berg Fund for Excellence in Immuno-Oncology Research. Dr. Greiling and Dr. Harris-Tryon reported having no relevant financial disclosures.
In the fall of 2020, Hassane M. Zarour, MD, and colleagues began to pore over raw data from their
Preclinical mouse studies have demonstrated that the gut microbiota could influence the response of tumors to anti–PD-1 immunotherapy, but FMT had not been previously evaluated in human patients with malignant melanoma whose disease persisted or progressed after medical therapy. Only 30%-40% of melanoma patients respond to anti–PD-1 immunotherapy, so the researchers’ sense of anticipation was palpable. “It’s a high-risk, high-reward study, so you never know,” Dr. Zarour, a dermatologist and immunologist who is coleader of the melanoma program at the University of Pittsburgh Medical Center’s Hillman Cancer Center, said in an interview.
For the study, which was funded by the National Institutes of Health and published in Science, Dr. Zarour and a team of colleagues, including Diwakar Davar, MD, a medical oncologist/hematologist at UPMC and Giorgio Trinchieri, MD, head of the cancer immunology section at the National Cancer Institute, enrolled 16 patients with advanced melanoma whose disease had persisted or progressed with anti-PD-1 drugs; donors were 7 patients with advanced melanoma who had responded to pembrolizumab, 4 with a complete response and 3 with a partial response, with a median progression-free survival of 56 months.
After donors and patients underwent serial stool sampling and studies to stamp out the potential for transmitting infectious agents, the researchers administered the donor-derived FMT to patients via colonoscopy every 14 days for 3 weeks, followed by pembrolizumab. To their delight, 6 of the 15 evaluable recipients responded to treatment, with a reduction in tumor or long-term disease stabilization. Moreover, responders also showed increased abundance of taxa that were previously associated with response to immunotherapy, increased activation of CD8+ T cells, and decreased frequency of interleukin-8–expressing myeloid cells.
“This opens new doors for the future,” Dr. Zarour said. “It’s very encouraging, but I don’t want to overstate the data. It’s a small, nonrandomized trial, but one has to keep in mind that people were skeptical about this work; they didn’t think FMT would work. Now we see many people coming into the field to investigate the role of the microbiome as a therapeutic tool, which is great.”
Teri Greiling, MD, characterized the finding as a key development in understanding the microbiome’s potential to influence the course of melanoma and other diseases. “What’s emerging over the last decade of research is that our immune system has a close, back-and-forth relationship with our microbiota,” said Dr. Greiling, associate professor of dermatology at Oregon Health & Science University, Portland. “From day 1 of birth, we’re colonized by microbes that train our immune system how to function. In response, your immune system keeps those microbes in check and shapes which ones are allowed to colonize, and which ones are a target for attack. Thus, inflammatory responses are generated. Similarly, the goal of immunotherapy is to activate the immune system to fight cancer. This study shows that the immune system continues to need the colonizing microbes in our body to function optimally.”
Immunotherapy with checkpoint inhibitors was not an option for malignant melanoma patients until 2011, she noted, so the potential for FMT to further improve outcomes is welcome news for patients and their families. “We went from a less than 5% chance of survival with metastatic melanoma to now, with the right combination of checkpoint inhibitors, we’re up over 50%, which is amazing in a decade,” Dr. Greiling said. “Still, we’re losing half of our patients. If [FMT provides] a 30% improvement over that, that would be great, but it’s hard to extrapolate from such small numbers.”
Positive results in an Israeli study
Results from a similar, smaller phase 1 trial of 2 FMT donors and 10 recipients with metastatic melanoma who had progressed on anti-PD-1 therapy, from the Ella Lemelbaum Institute for Immuno-Oncology at Sheba Medical Center in Tel HaShomer, Israel, yielded similar results. The FMT protocol in this study included colonoscopy and oral stool capsules, followed by the reintroduction of anti–PD-1 therapy with nivolumab. The two FMT donors had previously been treated with anti–PD-1 monotherapy for metastatic melanoma and had achieved a clinical response for at least 1 year. Of the 10 FMT recipients, 1 had a complete response and 2 had a partial response.
“We expected changes in the immune system but did not expect that 3 out of the 10 patients in our study would be turned from nonresponders to responders,” the study’s lead author, Erez N. Baruch, MD, PhD, told this news organization. “Since this was a first-in-human study, we were aiming to assess safety and not clinical responses. [We found] that microbiota modulation can change the immune infiltration within melanoma tumors and by this affect response to immunotherapy.”
Dr. Baruch, an internal medicine resident in the physician-scientist track program at the University of Texas, Houston, said that the findings create a potential new therapeutic paradigm, or a new “playing ground” for drug development that can support existing immunotherapies. “It is important for dermatologists to understand that disruptions of the gut microbiota, mainly by antibiotics, may be harmful to melanoma patients,” he said. “Antibiotics in cancer patients should be used judiciously but of course should not be avoided when there’s an indication.”
As for next steps, Dr. Zarour and colleagues are recruiting more patients to boost their sample size and conducting sequential analysis of the microbiome of study participants “to better determine what the good and bad bugs are,” he said. “There are so many variables, including diet and geography. We need more data.” The hope is to develop a “microbiome signature” to identify patients likely to respond to FMT, and maybe one day, a probiotic capsule that patients take to optimize their response to immunotherapy.
“We don’t want to say that the microbiome is responsible for everything, but it’s responsible for some of the response and some of the resistance to treatment,” Dr. Zarour said. “So, we want to identify what candidate nonresponders are more likely to respond to FMT and be able to stick the right stool in the donor. This goes to better education of the microbiome signature. We are working hard on that.”
Dr. Baruch added that performing FMT for melanoma patients requires tight collaborations between oncologists, dermatologists, GI, and infectious disease experts. “These usually can be done in the setting of large cancer centers and will probably not be available in any hospital,” he said. “This is why understanding the mechanisms and developing an FMT-like drug is important. We are focusing on studying the mechanisms behind the clinical effect in order to develop a drug with an FMT-like effect without the safety and logistic issues related to FMTs.”
Tamia A. Harris-Tryon, MD, PhD, whose lab at the University of Texas Southwestern Medical Center at Dallas is studying how diet and the microbiota impact skin immunity, underscored the importance of evaluating the characteristics of the diet of patients as trials of FMT in melanoma patients carry on. “We know that the diet impacts the repertoire of microbes that colonize the gut,” said Dr. Harris-Tryon, assistant professor in the department of dermatology at the medical center. “The diet of the recipient likely has an impact” on the success of donor FMT.
She also noted that other skin conditions have been linked to a disrupted gut microbiome, such as psoriasis. “Given the safety of FMT in both of these studies, trials of FMT in psoriasis and other systemic skin conditions should be considered,” she said.
According to Dr. Zarour, mounting data from separate studies show that some gut microbiota play a role in adverse events experienced by melanoma patients on immunotherapy. “That is very important, especially with combination therapy,” he said. “There are also microbes involved in resistance to treatment, so the idea would be to identify these microbes.”
Studies raise more questions
In the opinion of Dr. Greiling, results from these two studies raise more questions than they answer. “The big question ... is why and how does FMT work, and how can we make the response better?” she said. “Is there one particular gene product from one microbe that is the key magic ingredient, and we can harness this as a drug? More likely it’s a complex interplay between multiple bacterial species needed to direct the immune response. Is there a group of microbes that is the same from person to person, or is it more complex?”
Then there are pending regulatory concerns. “We know that FMT works for [Clostridioides] difficile colitis but it’s not officially [Food and Drug Administration] approved,” Dr. Greiling said. “The FDA is really struggling with how to approve or regulate using bacteria as a drug. Where is that crossover? That inhibits things moving forward, for good reason. You want to balance safety with live microbes.”
The UPMC clinical trial was supported by Merck. Dr. Zarour disclosed that he is supported by grants from the National Cancer Institute and the James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research at UPMC. The Israeli study was funded by the Ella Lemelbaum Institute for Immuno-Oncology. Dr. Baruch was supported by the Allen Berg Fund for Excellence in Immuno-Oncology Research. Dr. Greiling and Dr. Harris-Tryon reported having no relevant financial disclosures.
FDA OKs iPLEDGE change for gender-neutral language
The Food and Drug Administration has approved a modification to the isotretinoin risk-mitigation program to make it more inclusive for transgender patients.
Beginning on Dec. 13, 2021, Previously, there were three risk categories: females of reproductive potential, females not of reproductive potential, and males.
In recent years, dermatologists and others have advocated for the change, hoping to make the process more inclusive and less intrusive for their transgender patients.
Isotretinoin (Accutane, Absorica, Amnesteem, Claravis, others) has a high risk of severe birth defects, and has been linked with other health issues, making it crucial for those with the ability to become pregnant to take contraceptive precautions while on the medication. Under the iPLEDGE program, physicians, patients, and pharmacies prescribing, using, or dispensing the drug must all be registered, with requirements that include the use of two forms of an effective contraceptive and regular pregnancy testing for patients who can become pregnant.
The FDA had given notification in June 2018 that the REMS modification and labeling change would be required, replacing the gender-specific language with gender-neutral language, according to an FDA spokesperson. The change was based on feedback that the gender-specific language can be a barrier to access for some patients. The FDA approved the modification on Oct. 8.
Expert reactions
“This is an exciting and welcome change from the FDA on iPLEDGE that many dermatologists, myself included, have advocated for quite a few years,” Howa Yeung, MD, MSc, assistant professor of dermatology at Emory University, Atlanta, said in an interview.
In a report on the dermatologic care for lesbian, gay, bisexual, and transgender persons published in the Journal of the American Academy of Dermatology, Dr. Yeung and his colleagues noted that more than 10 million lesbian, gay, bisexual and transgender people live in the United States and that improving their health is a public health priority.
“For cisgender patients, nothing has changed – patients will continue to receive appropriate educational material related to isotretinoin based on their pregnancy potential,” Dr. Yeung said. “For transgender and gender diverse patients, this is a huge step forward.”
Under the previous system, doctors were asked to register patients using gender binary categories, “which were confusing when they did not reflect reality” for these patients, Dr. Yeung said. The new system, Dr. Yeung added, “will make my job easier. I no longer have to struggle between respecting the patient’s gender identity and providing medically necessary care for patients with severe acne.”
“The new terminology is not just respectful, it also is simpler and makes more sense,” agreed Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery at Mount Sinai Health System and professor of medicine at the Icahn School of Medicine at Mount Sinai, New York. “As it stood, a transgender man with his uterus and ovaries in place might be missed in the pregnancy surveillance system because he could simply be labeled a man and not followed further. At the same time, both transgender women and cisgender women who were at no risk of pregnancy could be subject to more medical scrutiny that might have been consider intrusive.”
The change “validates the important point that pregnancy potential is not exclusively defined by sociocultural constructs of gender and allow dermatologists to focus purely on what matters when prescribing isotretinoin – whether an individual is able to become pregnant or not, regardless of their gender identity,” Klint Peebles, MD, a dermatologist at Kaiser Permanente in Washington, D.C., and suburban Maryland, who has also advocated for the change, said in an interview.
FDA elaborates
The modification includes important changes for doctors, pharmacists, and patients alike, according to the FDA.
Health care providers must assign and confirm their currently enrolled patient’s risk category when they first log in to the IPLEDGE REMS website on or after Dec. 13, the effective date. They should be sure any patient whose prescription RMA (iPLEDGE authorization) expires on Dec. 11-12 is told to obtain their prescription before midnight, Eastern time, Dec. 10.
Pharmacists will be affected, too, since the iPLEDGE REMS changed to a new platform vendor and the current “switch” pharmacy management system will be removed as a method to verify authorization to dispense isotretinoin. With these changes, as of Dec. 13, pharmacists can’t use the switch system to obtain a predispense authorization, or RMA (risk management authorization). They will need to obtain an RMA online by accessing the iPLEDGE REMS website or via telephone to the PLEDGE REMS center, 866-495-0654, before dispensing the prescription.
Patients, beginning Dec. 13, will have the option of presenting a unique QR code at the pharmacy on their smartphone rather than providing the iPLEDGE identification number. The code can be accessed by logging into their account on the iPLEDGE REMS website.
Patients with an isotretinoin prescription RMA that expires Dec. 11-12, must obtain the prescription before 11:59 p.m. Eastern time on Dec. 10. If the RMA expires before the prescription is picked up, the patient must begin the authorization process all over again.
Dr. Safer, Dr. Yeung, and Dr. Peebles have no relevant disclosures.
More information on the update and the isotretinoin REMS program is available on the FDA website.
The Food and Drug Administration has approved a modification to the isotretinoin risk-mitigation program to make it more inclusive for transgender patients.
Beginning on Dec. 13, 2021, Previously, there were three risk categories: females of reproductive potential, females not of reproductive potential, and males.
In recent years, dermatologists and others have advocated for the change, hoping to make the process more inclusive and less intrusive for their transgender patients.
Isotretinoin (Accutane, Absorica, Amnesteem, Claravis, others) has a high risk of severe birth defects, and has been linked with other health issues, making it crucial for those with the ability to become pregnant to take contraceptive precautions while on the medication. Under the iPLEDGE program, physicians, patients, and pharmacies prescribing, using, or dispensing the drug must all be registered, with requirements that include the use of two forms of an effective contraceptive and regular pregnancy testing for patients who can become pregnant.
The FDA had given notification in June 2018 that the REMS modification and labeling change would be required, replacing the gender-specific language with gender-neutral language, according to an FDA spokesperson. The change was based on feedback that the gender-specific language can be a barrier to access for some patients. The FDA approved the modification on Oct. 8.
Expert reactions
“This is an exciting and welcome change from the FDA on iPLEDGE that many dermatologists, myself included, have advocated for quite a few years,” Howa Yeung, MD, MSc, assistant professor of dermatology at Emory University, Atlanta, said in an interview.
In a report on the dermatologic care for lesbian, gay, bisexual, and transgender persons published in the Journal of the American Academy of Dermatology, Dr. Yeung and his colleagues noted that more than 10 million lesbian, gay, bisexual and transgender people live in the United States and that improving their health is a public health priority.
“For cisgender patients, nothing has changed – patients will continue to receive appropriate educational material related to isotretinoin based on their pregnancy potential,” Dr. Yeung said. “For transgender and gender diverse patients, this is a huge step forward.”
Under the previous system, doctors were asked to register patients using gender binary categories, “which were confusing when they did not reflect reality” for these patients, Dr. Yeung said. The new system, Dr. Yeung added, “will make my job easier. I no longer have to struggle between respecting the patient’s gender identity and providing medically necessary care for patients with severe acne.”
“The new terminology is not just respectful, it also is simpler and makes more sense,” agreed Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery at Mount Sinai Health System and professor of medicine at the Icahn School of Medicine at Mount Sinai, New York. “As it stood, a transgender man with his uterus and ovaries in place might be missed in the pregnancy surveillance system because he could simply be labeled a man and not followed further. At the same time, both transgender women and cisgender women who were at no risk of pregnancy could be subject to more medical scrutiny that might have been consider intrusive.”
The change “validates the important point that pregnancy potential is not exclusively defined by sociocultural constructs of gender and allow dermatologists to focus purely on what matters when prescribing isotretinoin – whether an individual is able to become pregnant or not, regardless of their gender identity,” Klint Peebles, MD, a dermatologist at Kaiser Permanente in Washington, D.C., and suburban Maryland, who has also advocated for the change, said in an interview.
FDA elaborates
The modification includes important changes for doctors, pharmacists, and patients alike, according to the FDA.
Health care providers must assign and confirm their currently enrolled patient’s risk category when they first log in to the IPLEDGE REMS website on or after Dec. 13, the effective date. They should be sure any patient whose prescription RMA (iPLEDGE authorization) expires on Dec. 11-12 is told to obtain their prescription before midnight, Eastern time, Dec. 10.
Pharmacists will be affected, too, since the iPLEDGE REMS changed to a new platform vendor and the current “switch” pharmacy management system will be removed as a method to verify authorization to dispense isotretinoin. With these changes, as of Dec. 13, pharmacists can’t use the switch system to obtain a predispense authorization, or RMA (risk management authorization). They will need to obtain an RMA online by accessing the iPLEDGE REMS website or via telephone to the PLEDGE REMS center, 866-495-0654, before dispensing the prescription.
Patients, beginning Dec. 13, will have the option of presenting a unique QR code at the pharmacy on their smartphone rather than providing the iPLEDGE identification number. The code can be accessed by logging into their account on the iPLEDGE REMS website.
Patients with an isotretinoin prescription RMA that expires Dec. 11-12, must obtain the prescription before 11:59 p.m. Eastern time on Dec. 10. If the RMA expires before the prescription is picked up, the patient must begin the authorization process all over again.
Dr. Safer, Dr. Yeung, and Dr. Peebles have no relevant disclosures.
More information on the update and the isotretinoin REMS program is available on the FDA website.
The Food and Drug Administration has approved a modification to the isotretinoin risk-mitigation program to make it more inclusive for transgender patients.
Beginning on Dec. 13, 2021, Previously, there were three risk categories: females of reproductive potential, females not of reproductive potential, and males.
In recent years, dermatologists and others have advocated for the change, hoping to make the process more inclusive and less intrusive for their transgender patients.
Isotretinoin (Accutane, Absorica, Amnesteem, Claravis, others) has a high risk of severe birth defects, and has been linked with other health issues, making it crucial for those with the ability to become pregnant to take contraceptive precautions while on the medication. Under the iPLEDGE program, physicians, patients, and pharmacies prescribing, using, or dispensing the drug must all be registered, with requirements that include the use of two forms of an effective contraceptive and regular pregnancy testing for patients who can become pregnant.
The FDA had given notification in June 2018 that the REMS modification and labeling change would be required, replacing the gender-specific language with gender-neutral language, according to an FDA spokesperson. The change was based on feedback that the gender-specific language can be a barrier to access for some patients. The FDA approved the modification on Oct. 8.
Expert reactions
“This is an exciting and welcome change from the FDA on iPLEDGE that many dermatologists, myself included, have advocated for quite a few years,” Howa Yeung, MD, MSc, assistant professor of dermatology at Emory University, Atlanta, said in an interview.
In a report on the dermatologic care for lesbian, gay, bisexual, and transgender persons published in the Journal of the American Academy of Dermatology, Dr. Yeung and his colleagues noted that more than 10 million lesbian, gay, bisexual and transgender people live in the United States and that improving their health is a public health priority.
“For cisgender patients, nothing has changed – patients will continue to receive appropriate educational material related to isotretinoin based on their pregnancy potential,” Dr. Yeung said. “For transgender and gender diverse patients, this is a huge step forward.”
Under the previous system, doctors were asked to register patients using gender binary categories, “which were confusing when they did not reflect reality” for these patients, Dr. Yeung said. The new system, Dr. Yeung added, “will make my job easier. I no longer have to struggle between respecting the patient’s gender identity and providing medically necessary care for patients with severe acne.”
“The new terminology is not just respectful, it also is simpler and makes more sense,” agreed Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery at Mount Sinai Health System and professor of medicine at the Icahn School of Medicine at Mount Sinai, New York. “As it stood, a transgender man with his uterus and ovaries in place might be missed in the pregnancy surveillance system because he could simply be labeled a man and not followed further. At the same time, both transgender women and cisgender women who were at no risk of pregnancy could be subject to more medical scrutiny that might have been consider intrusive.”
The change “validates the important point that pregnancy potential is not exclusively defined by sociocultural constructs of gender and allow dermatologists to focus purely on what matters when prescribing isotretinoin – whether an individual is able to become pregnant or not, regardless of their gender identity,” Klint Peebles, MD, a dermatologist at Kaiser Permanente in Washington, D.C., and suburban Maryland, who has also advocated for the change, said in an interview.
FDA elaborates
The modification includes important changes for doctors, pharmacists, and patients alike, according to the FDA.
Health care providers must assign and confirm their currently enrolled patient’s risk category when they first log in to the IPLEDGE REMS website on or after Dec. 13, the effective date. They should be sure any patient whose prescription RMA (iPLEDGE authorization) expires on Dec. 11-12 is told to obtain their prescription before midnight, Eastern time, Dec. 10.
Pharmacists will be affected, too, since the iPLEDGE REMS changed to a new platform vendor and the current “switch” pharmacy management system will be removed as a method to verify authorization to dispense isotretinoin. With these changes, as of Dec. 13, pharmacists can’t use the switch system to obtain a predispense authorization, or RMA (risk management authorization). They will need to obtain an RMA online by accessing the iPLEDGE REMS website or via telephone to the PLEDGE REMS center, 866-495-0654, before dispensing the prescription.
Patients, beginning Dec. 13, will have the option of presenting a unique QR code at the pharmacy on their smartphone rather than providing the iPLEDGE identification number. The code can be accessed by logging into their account on the iPLEDGE REMS website.
Patients with an isotretinoin prescription RMA that expires Dec. 11-12, must obtain the prescription before 11:59 p.m. Eastern time on Dec. 10. If the RMA expires before the prescription is picked up, the patient must begin the authorization process all over again.
Dr. Safer, Dr. Yeung, and Dr. Peebles have no relevant disclosures.
More information on the update and the isotretinoin REMS program is available on the FDA website.
9-step ladder may kids with allergies return to eggs
For many children in the process of outgrowing egg allergy, the step-wise reintroduction of foods that contain eggs can be achieved at home using a nine-rung laddered approach, according to updated guidelines from the British Society for Allergy and Clinical Immunology (BSACI).
Attempts to reintroduce egg into the child’s diet can start at the age of 12 months or 6 months from the last reaction, as long as past reactions have been mild to moderate and the child does not have asthma, according to guidelines from the BSACI, which represents allergists, pediatricians, and other health care practitioners.
According to the guidelines, the reintroduction needs to be guided by a specialist allergy service for children who have had severe reactions to egg or who have asthma.
Susan C. Leech, MB BChir, DCH, first author of the guidelines and a consultant in pediatric allergy with the Department of Child Health at Kings College Hospital, London, told this news organization that home reintroduction should begin slowly with small amounts of baked egg, starting with a pea-sized piece of cake, and should proceed gradually.
“Parents can be reassured that it’s a relatively safe thing to do as long as it’s done with caution,” said Dr. Leech.
The expanded guidelines include a new nine-step reintroduction ladder. It builds on a three-stage classification of egg-containing foods that was first introduced in BSACI guidelines in 2010.
On the bottom four rungs, children work their way through small but increasing amounts of fairy cakes (cupcakes), biscuits (cookies), and other foods containing baked eggs.
The next three rungs involve hard-boiled eggs, quiche, and other well-cooked egg products.
At the eighth rung, children can have small mouthfuls of runny scrambled eggs, mayonnaise, and other less-cooked or raw egg-containing products. At the top rung, children can have increasing amounts of those products as well as licks of cake batter.
The guidelines were published online September 29 in Clinical and Experimental Allergy along with a supplement that includes a series of examples showing how the guidelines apply to specific patient cases.
“These are examples only,” the guideline authors caution in the appendix. “Clinical judgment of severity is important as risk assessment is not always easy.”
Anna Nowak-Wegrzyn, MD, PhD, a professor of pediatrics at NYU Grossman School of Medicine and chief of pediatric allergy and immunology for Hassenfeld Children’s Hospital at NYU Langone, who was not involved in the BSACI guidelines, described the egg ladder as a “proactive” strategy that deserves further study and consideration.
“I think that this may be a valid approach,” said Dr. Nowak-Wegrzyn in an interview. “Eggs have good nutritional value, and they are present in a lot of foods, so avoidance creates logistical challenges.”
Using the egg ladder for home-based reintroduction may be especially suited in resource-poor areas where access to an allergist may be difficult, she said. It may also be suited for families that can’t visit the office because of pandemic-related restrictions.
“If the child had a severe reaction or if they have asthma, then it’s a no-go,” she added, “but if you have a patient who has a really mild reaction and you think that overall the risk of a significant reaction or bad symptoms is low, then it may be worth doing.”
Dr. Leech and Dr. Nowak-Wegrzyn have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
For many children in the process of outgrowing egg allergy, the step-wise reintroduction of foods that contain eggs can be achieved at home using a nine-rung laddered approach, according to updated guidelines from the British Society for Allergy and Clinical Immunology (BSACI).
Attempts to reintroduce egg into the child’s diet can start at the age of 12 months or 6 months from the last reaction, as long as past reactions have been mild to moderate and the child does not have asthma, according to guidelines from the BSACI, which represents allergists, pediatricians, and other health care practitioners.
According to the guidelines, the reintroduction needs to be guided by a specialist allergy service for children who have had severe reactions to egg or who have asthma.
Susan C. Leech, MB BChir, DCH, first author of the guidelines and a consultant in pediatric allergy with the Department of Child Health at Kings College Hospital, London, told this news organization that home reintroduction should begin slowly with small amounts of baked egg, starting with a pea-sized piece of cake, and should proceed gradually.
“Parents can be reassured that it’s a relatively safe thing to do as long as it’s done with caution,” said Dr. Leech.
The expanded guidelines include a new nine-step reintroduction ladder. It builds on a three-stage classification of egg-containing foods that was first introduced in BSACI guidelines in 2010.
On the bottom four rungs, children work their way through small but increasing amounts of fairy cakes (cupcakes), biscuits (cookies), and other foods containing baked eggs.
The next three rungs involve hard-boiled eggs, quiche, and other well-cooked egg products.
At the eighth rung, children can have small mouthfuls of runny scrambled eggs, mayonnaise, and other less-cooked or raw egg-containing products. At the top rung, children can have increasing amounts of those products as well as licks of cake batter.
The guidelines were published online September 29 in Clinical and Experimental Allergy along with a supplement that includes a series of examples showing how the guidelines apply to specific patient cases.
“These are examples only,” the guideline authors caution in the appendix. “Clinical judgment of severity is important as risk assessment is not always easy.”
Anna Nowak-Wegrzyn, MD, PhD, a professor of pediatrics at NYU Grossman School of Medicine and chief of pediatric allergy and immunology for Hassenfeld Children’s Hospital at NYU Langone, who was not involved in the BSACI guidelines, described the egg ladder as a “proactive” strategy that deserves further study and consideration.
“I think that this may be a valid approach,” said Dr. Nowak-Wegrzyn in an interview. “Eggs have good nutritional value, and they are present in a lot of foods, so avoidance creates logistical challenges.”
Using the egg ladder for home-based reintroduction may be especially suited in resource-poor areas where access to an allergist may be difficult, she said. It may also be suited for families that can’t visit the office because of pandemic-related restrictions.
“If the child had a severe reaction or if they have asthma, then it’s a no-go,” she added, “but if you have a patient who has a really mild reaction and you think that overall the risk of a significant reaction or bad symptoms is low, then it may be worth doing.”
Dr. Leech and Dr. Nowak-Wegrzyn have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
For many children in the process of outgrowing egg allergy, the step-wise reintroduction of foods that contain eggs can be achieved at home using a nine-rung laddered approach, according to updated guidelines from the British Society for Allergy and Clinical Immunology (BSACI).
Attempts to reintroduce egg into the child’s diet can start at the age of 12 months or 6 months from the last reaction, as long as past reactions have been mild to moderate and the child does not have asthma, according to guidelines from the BSACI, which represents allergists, pediatricians, and other health care practitioners.
According to the guidelines, the reintroduction needs to be guided by a specialist allergy service for children who have had severe reactions to egg or who have asthma.
Susan C. Leech, MB BChir, DCH, first author of the guidelines and a consultant in pediatric allergy with the Department of Child Health at Kings College Hospital, London, told this news organization that home reintroduction should begin slowly with small amounts of baked egg, starting with a pea-sized piece of cake, and should proceed gradually.
“Parents can be reassured that it’s a relatively safe thing to do as long as it’s done with caution,” said Dr. Leech.
The expanded guidelines include a new nine-step reintroduction ladder. It builds on a three-stage classification of egg-containing foods that was first introduced in BSACI guidelines in 2010.
On the bottom four rungs, children work their way through small but increasing amounts of fairy cakes (cupcakes), biscuits (cookies), and other foods containing baked eggs.
The next three rungs involve hard-boiled eggs, quiche, and other well-cooked egg products.
At the eighth rung, children can have small mouthfuls of runny scrambled eggs, mayonnaise, and other less-cooked or raw egg-containing products. At the top rung, children can have increasing amounts of those products as well as licks of cake batter.
The guidelines were published online September 29 in Clinical and Experimental Allergy along with a supplement that includes a series of examples showing how the guidelines apply to specific patient cases.
“These are examples only,” the guideline authors caution in the appendix. “Clinical judgment of severity is important as risk assessment is not always easy.”
Anna Nowak-Wegrzyn, MD, PhD, a professor of pediatrics at NYU Grossman School of Medicine and chief of pediatric allergy and immunology for Hassenfeld Children’s Hospital at NYU Langone, who was not involved in the BSACI guidelines, described the egg ladder as a “proactive” strategy that deserves further study and consideration.
“I think that this may be a valid approach,” said Dr. Nowak-Wegrzyn in an interview. “Eggs have good nutritional value, and they are present in a lot of foods, so avoidance creates logistical challenges.”
Using the egg ladder for home-based reintroduction may be especially suited in resource-poor areas where access to an allergist may be difficult, she said. It may also be suited for families that can’t visit the office because of pandemic-related restrictions.
“If the child had a severe reaction or if they have asthma, then it’s a no-go,” she added, “but if you have a patient who has a really mild reaction and you think that overall the risk of a significant reaction or bad symptoms is low, then it may be worth doing.”
Dr. Leech and Dr. Nowak-Wegrzyn have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Study of biologics’ impact on psoriasis-to-PsA transition contradicts previous findings
Data source likely contributes biases
A new study has found that patients with psoriasis who were treated with biologics were more likely to develop psoriatic arthritis (PsA) than those treated with phototherapy, oral therapy, or no therapy at all, although the authors cautioned readers to consider potential biases when reviewing their findings.
“We do not suggest that these results should be interpreted causally; in other words, biologics likely do not cause PsA,” Elana Meer of the University of Pennsylvania, Philadelphia, and coauthors wrote. The study was published in Annals of the Rheumatic Diseases.
Three studies in dermatology clinic-based populations published this past summer – one from Italy, one from Argentina, and one from Israel – suggested that biologics can decrease a psoriasis patient’s risk of developing PsA. To further assess the impact of treatment with biologics, Ms. Meer and associates retrospectively examined the health records of thousands of patients with psoriasis between the ages of 16 and 90 who were initiating therapy. All told, data from 193,709 patients with psoriasis and without PsA who were treated between 2006 and 2017 were gathered from the OptumInsights Electronic Health Record Database.
A total of 14,569 patients from that cohort initiated biologic therapy while 20,321 patients initiated either oral therapy or phototherapy. The mean age in the biologics group was 45.9 years, compared with 49.8 years in the oral and phototherapy group.
The incidence of PsA across all patients was 9.75 cases per 1,000 person-years, compared with 77.26 among the biologic group, 61.99 among the oral therapy group, 26.11 among the phototherapy group, and 5.85 among those who did not receive therapy. After a multivariable adjustment in which biologics were a time-varying exposure, receiving biologics was associated with a higher incidence of PsA (hazard ratio, 4.48; 95% confidence interval, 4.23-4.75). In a model where time starts at the first use of biologics, the incidence was lower – but still notable – after multivariable adjustment (HR, 2.14; 95% CI, 2.00-2.28) and propensity score matching (HR, 2.17; 95% CI, 2.03-2.33).
Bias likely plays a large role in retrospective PsA study
“We’ve been struggling for the last several years to find a database that allows us to really address this question retrospectively,” study coauthor Christopher T. Ritchlin, MD, of the University of Rochester (N.Y.), said in an interview. “It looks like the model you use for a retrospective analysis heavily influences what you come out with.”
He described the potential biases they identified, including the possibility of protopathic bias indicating that patients being treated with biologics who then report joint pain have developed PsA – and are coded accordingly after visiting a rheumatologist.
“This has convinced us that you have to do a prospective study,” he said. “We’ve known that there were flaws with previous studies in this area. We tried to overcome them with our methodology, but there’s no way you can overcome a coding issue when you’re looking at such a large database.”
He noted another likely bias: The patients who are more likely to develop PsA are the ones with severe psoriasis, and they are also the patients most likely to be prescribed biologics.
“In my clinical experience, I have seen many patients develop psoriatic arthritis while on biologics for their psoriasis,” coauthor Joel M. Gelfand, MD, of the University of Pennsylvania, added in an interview. “Currently, we do not have adequate data to recommend treating psoriasis with a particular modality in order to prevent psoriatic arthritis. This question, however, is very important to patients and clinicians and ultimately is best answered with a large-scale pragmatic trial.”
Dr. Ritchlin reported that a prospective study in which “patients with psoriasis who do not have arthritis but do have certain risk factors and abnormal findings on musculoskeletal ultrasounds” will be treated with either biologic agents or placebo is about to begin, with a goal of “either attenuating or preventing the onset of PsA.”
The authors recognized their study’s additional limitations, including electronic health records being used as the primary data source and the possibility that medications were prescribed but never filled. That said, they did attempt to address the latter by using two prescriptions for a given therapy as the primary analysis, “suggesting a refill was initiated.”
The authors said that no commercial entities provided support for the study. Two of the authors acknowledged receiving funding from the National Psoriasis Foundation, and several authors declared potential conflicts of interests that included consulting and receiving honoraria from various pharmaceutical companies.
Data source likely contributes biases
Data source likely contributes biases
A new study has found that patients with psoriasis who were treated with biologics were more likely to develop psoriatic arthritis (PsA) than those treated with phototherapy, oral therapy, or no therapy at all, although the authors cautioned readers to consider potential biases when reviewing their findings.
“We do not suggest that these results should be interpreted causally; in other words, biologics likely do not cause PsA,” Elana Meer of the University of Pennsylvania, Philadelphia, and coauthors wrote. The study was published in Annals of the Rheumatic Diseases.
Three studies in dermatology clinic-based populations published this past summer – one from Italy, one from Argentina, and one from Israel – suggested that biologics can decrease a psoriasis patient’s risk of developing PsA. To further assess the impact of treatment with biologics, Ms. Meer and associates retrospectively examined the health records of thousands of patients with psoriasis between the ages of 16 and 90 who were initiating therapy. All told, data from 193,709 patients with psoriasis and without PsA who were treated between 2006 and 2017 were gathered from the OptumInsights Electronic Health Record Database.
A total of 14,569 patients from that cohort initiated biologic therapy while 20,321 patients initiated either oral therapy or phototherapy. The mean age in the biologics group was 45.9 years, compared with 49.8 years in the oral and phototherapy group.
The incidence of PsA across all patients was 9.75 cases per 1,000 person-years, compared with 77.26 among the biologic group, 61.99 among the oral therapy group, 26.11 among the phototherapy group, and 5.85 among those who did not receive therapy. After a multivariable adjustment in which biologics were a time-varying exposure, receiving biologics was associated with a higher incidence of PsA (hazard ratio, 4.48; 95% confidence interval, 4.23-4.75). In a model where time starts at the first use of biologics, the incidence was lower – but still notable – after multivariable adjustment (HR, 2.14; 95% CI, 2.00-2.28) and propensity score matching (HR, 2.17; 95% CI, 2.03-2.33).
Bias likely plays a large role in retrospective PsA study
“We’ve been struggling for the last several years to find a database that allows us to really address this question retrospectively,” study coauthor Christopher T. Ritchlin, MD, of the University of Rochester (N.Y.), said in an interview. “It looks like the model you use for a retrospective analysis heavily influences what you come out with.”
He described the potential biases they identified, including the possibility of protopathic bias indicating that patients being treated with biologics who then report joint pain have developed PsA – and are coded accordingly after visiting a rheumatologist.
“This has convinced us that you have to do a prospective study,” he said. “We’ve known that there were flaws with previous studies in this area. We tried to overcome them with our methodology, but there’s no way you can overcome a coding issue when you’re looking at such a large database.”
He noted another likely bias: The patients who are more likely to develop PsA are the ones with severe psoriasis, and they are also the patients most likely to be prescribed biologics.
“In my clinical experience, I have seen many patients develop psoriatic arthritis while on biologics for their psoriasis,” coauthor Joel M. Gelfand, MD, of the University of Pennsylvania, added in an interview. “Currently, we do not have adequate data to recommend treating psoriasis with a particular modality in order to prevent psoriatic arthritis. This question, however, is very important to patients and clinicians and ultimately is best answered with a large-scale pragmatic trial.”
Dr. Ritchlin reported that a prospective study in which “patients with psoriasis who do not have arthritis but do have certain risk factors and abnormal findings on musculoskeletal ultrasounds” will be treated with either biologic agents or placebo is about to begin, with a goal of “either attenuating or preventing the onset of PsA.”
The authors recognized their study’s additional limitations, including electronic health records being used as the primary data source and the possibility that medications were prescribed but never filled. That said, they did attempt to address the latter by using two prescriptions for a given therapy as the primary analysis, “suggesting a refill was initiated.”
The authors said that no commercial entities provided support for the study. Two of the authors acknowledged receiving funding from the National Psoriasis Foundation, and several authors declared potential conflicts of interests that included consulting and receiving honoraria from various pharmaceutical companies.
A new study has found that patients with psoriasis who were treated with biologics were more likely to develop psoriatic arthritis (PsA) than those treated with phototherapy, oral therapy, or no therapy at all, although the authors cautioned readers to consider potential biases when reviewing their findings.
“We do not suggest that these results should be interpreted causally; in other words, biologics likely do not cause PsA,” Elana Meer of the University of Pennsylvania, Philadelphia, and coauthors wrote. The study was published in Annals of the Rheumatic Diseases.
Three studies in dermatology clinic-based populations published this past summer – one from Italy, one from Argentina, and one from Israel – suggested that biologics can decrease a psoriasis patient’s risk of developing PsA. To further assess the impact of treatment with biologics, Ms. Meer and associates retrospectively examined the health records of thousands of patients with psoriasis between the ages of 16 and 90 who were initiating therapy. All told, data from 193,709 patients with psoriasis and without PsA who were treated between 2006 and 2017 were gathered from the OptumInsights Electronic Health Record Database.
A total of 14,569 patients from that cohort initiated biologic therapy while 20,321 patients initiated either oral therapy or phototherapy. The mean age in the biologics group was 45.9 years, compared with 49.8 years in the oral and phototherapy group.
The incidence of PsA across all patients was 9.75 cases per 1,000 person-years, compared with 77.26 among the biologic group, 61.99 among the oral therapy group, 26.11 among the phototherapy group, and 5.85 among those who did not receive therapy. After a multivariable adjustment in which biologics were a time-varying exposure, receiving biologics was associated with a higher incidence of PsA (hazard ratio, 4.48; 95% confidence interval, 4.23-4.75). In a model where time starts at the first use of biologics, the incidence was lower – but still notable – after multivariable adjustment (HR, 2.14; 95% CI, 2.00-2.28) and propensity score matching (HR, 2.17; 95% CI, 2.03-2.33).
Bias likely plays a large role in retrospective PsA study
“We’ve been struggling for the last several years to find a database that allows us to really address this question retrospectively,” study coauthor Christopher T. Ritchlin, MD, of the University of Rochester (N.Y.), said in an interview. “It looks like the model you use for a retrospective analysis heavily influences what you come out with.”
He described the potential biases they identified, including the possibility of protopathic bias indicating that patients being treated with biologics who then report joint pain have developed PsA – and are coded accordingly after visiting a rheumatologist.
“This has convinced us that you have to do a prospective study,” he said. “We’ve known that there were flaws with previous studies in this area. We tried to overcome them with our methodology, but there’s no way you can overcome a coding issue when you’re looking at such a large database.”
He noted another likely bias: The patients who are more likely to develop PsA are the ones with severe psoriasis, and they are also the patients most likely to be prescribed biologics.
“In my clinical experience, I have seen many patients develop psoriatic arthritis while on biologics for their psoriasis,” coauthor Joel M. Gelfand, MD, of the University of Pennsylvania, added in an interview. “Currently, we do not have adequate data to recommend treating psoriasis with a particular modality in order to prevent psoriatic arthritis. This question, however, is very important to patients and clinicians and ultimately is best answered with a large-scale pragmatic trial.”
Dr. Ritchlin reported that a prospective study in which “patients with psoriasis who do not have arthritis but do have certain risk factors and abnormal findings on musculoskeletal ultrasounds” will be treated with either biologic agents or placebo is about to begin, with a goal of “either attenuating or preventing the onset of PsA.”
The authors recognized their study’s additional limitations, including electronic health records being used as the primary data source and the possibility that medications were prescribed but never filled. That said, they did attempt to address the latter by using two prescriptions for a given therapy as the primary analysis, “suggesting a refill was initiated.”
The authors said that no commercial entities provided support for the study. Two of the authors acknowledged receiving funding from the National Psoriasis Foundation, and several authors declared potential conflicts of interests that included consulting and receiving honoraria from various pharmaceutical companies.
FROM ANNALS OF THE RHEUMATIC DISEASES
PDT for actinic keratoses continues to be refined
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“We have conventional PDT, daylight PDT; we can combine with a range of topicals, and we can combine a range of different physical treatment procedures in order to provide better and individualized treatment regimens for our patients,” Merete Haedersdal, MD, PhD, DMSc, professor of dermatology at the University of Copenhagen, said during a course on laser and aesthetic skin therapy.
In Europe, PDT consists of a three-step procedure: curettage of AKs, application of photosensitizer on the skin (typically methyl aminolevulinate, versus aminolevulinic acid, used more often in the United States), and illumination with red light (versus blue light, used more often in the United States), which causes a photochemical reaction.
“It’s a photochemical-reaction concept with which we can achieve up to 90% cure rates of AKs at 3 months,” Dr. Haedersdal said during the meeting, which was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine.
PDT is also used in Europe for select patients with Bowen’s disease (yielding a 90% cure rate at 3 months, 70% at 2 years); superficial basal cell carcinoma (yielding a 90% cure rate at 3 months, 75% at 5 years), and nodular BCC (yielding a 90% cure rate at 3 months, 75% at 5 years.
“With conventional PDT, whether it’s blue light, red light, MAL, or ALA, we have beautiful cosmesis, but we also have a challenge, which is pain,” she said. This is behind the motivation to look at other ways to provide PDT.
Daylight PDT, which was pioneered by Dr. Haedersdal’s mentor, Hans Christian Wulf, MD, DMSc, PharmD, professor of dermatology at the University of Copenhagen, provides 80%-90% clearance of thin AKs, lower clearance of thick AKs – and is a nearly pain-free procedure because of continuous photoactivation of protoporphyrin IX, with a Visual Analog Scale in the range of 1-3. “Globally, thousands of patients have been treated [with daylight PDT], which is backed up in the literature with more than 150 publications,” she said.
According to Dr. Haedersdal, MAL cream with daylight activation for treatment of AK was approved in Colombia and Mexico in 2013; in Australia, Brazil, and Costa Rica in 2014; and in Chile, Europe, and New Zealand in 2015. “I do hope that one day you will have daylight PDT approved in the United States,” she said.
The suggested protocol for daylight PDT starts by applying a sunscreen with an organic filter. After about 15 minutes, the lesion or lesions are prepared, and MAL is applied with no occlusion. Patients should start their exposure to daylight within 30 minutes of application, remaining outdoors for 2 hours of continuous exposure, either at a dedicated space located on the ground of the hospital or clinic or at their home. After 2 hours, patients wipe off the remaining cream and are advised to stay indoors for the rest of the day.
“Ideal candidates are those who have large skin areas that can be easily exposed to sunlight,” such as the scalp and lower legs, said Dr. Haedersdal, who is also a visiting scientist at the Wellman Center for Photomedicine, Boston. “If patients are treated in areas covered by clothing, it can be greasy and sticky with the cream. In these cases, you can cover the area with Tegaderm, which allows for 99% light transmission. Daylight can shine through and the Tegaderm can be removed after the procedure.”
On rainy days between April 1 and October 1 in Copenhagen, she said, daylight PDT is provided in a greenhouse in the hospital garden, with a heater and blankets for patients when the temperature falls below 10° C.
The amount of light required for a treatment effect is 5,000-10,000 lux, and the number of lux on a sunny day in Denmark is about 100,000, she said. “That means that all year round in countries south of latitude 45 degrees N, patients can be treated with daylight PDT.”
To intensify the treatment efficacy of conventional PDT and daylight PDT, especially in those with severely photodamaged skin, combining treatment with a physical pretreatment technique such as curettage, ablative fractional laser, microdermabrasion, microneedling, and nonablative fractional laser is another strategy. A small randomized controlled trial found that ablative fractional laser treatment extended notable relative effectiveness, compared with other physical enhancement techniques.
Dr. Haedersdal and colleagues published a study that compared pretreatment with ablative fractional laser and microdermabrasion pads before daylight PDT for AKs in field-cancerized skin. They found that with a single treatment, combination therapy with ablative fractional laser before daylight PDT led to significantly greater efficacious AK clearance and skin rejuvenation, compared with treatment with microdermabrasion.
“We don’t know why this is, but we believe it may be due to the fact that with the laser, we have a photothermal response, which in combination with the photochemical response from the photodynamic therapy induces a synergistic effect,” she said.
A range of topical treatments can also be given in combination with PDT. In a meta-analysis of 10 randomized controlled trials, German researchers evaluated the efficacy of PDT combined with imiquimod cream, 5-fluorouracil cream, tazarotene gel, and calcipotriol ointment. They concluded that the combination of PDT with another topical drug intervention improves AK clearance rates, compared with monotherapy.
More recently, the same authors summarized the current knowledge on the efficacy and safety of local combination therapies for the treatment of patients with AK in a review article, which Dr. Haedersdal said provides a nice overview of this topic.
Dr. Haedersdal disclosed that she has received equipment from Cherry Imaging, Cynosure-Hologic, MiraDry, and PerfAction Technologies. She has also received research grants from Leo Pharma, Lutronic, Mirai Medical, Novoxel, and Venus Concept.
.
“We have conventional PDT, daylight PDT; we can combine with a range of topicals, and we can combine a range of different physical treatment procedures in order to provide better and individualized treatment regimens for our patients,” Merete Haedersdal, MD, PhD, DMSc, professor of dermatology at the University of Copenhagen, said during a course on laser and aesthetic skin therapy.
In Europe, PDT consists of a three-step procedure: curettage of AKs, application of photosensitizer on the skin (typically methyl aminolevulinate, versus aminolevulinic acid, used more often in the United States), and illumination with red light (versus blue light, used more often in the United States), which causes a photochemical reaction.
“It’s a photochemical-reaction concept with which we can achieve up to 90% cure rates of AKs at 3 months,” Dr. Haedersdal said during the meeting, which was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine.
PDT is also used in Europe for select patients with Bowen’s disease (yielding a 90% cure rate at 3 months, 70% at 2 years); superficial basal cell carcinoma (yielding a 90% cure rate at 3 months, 75% at 5 years), and nodular BCC (yielding a 90% cure rate at 3 months, 75% at 5 years.
“With conventional PDT, whether it’s blue light, red light, MAL, or ALA, we have beautiful cosmesis, but we also have a challenge, which is pain,” she said. This is behind the motivation to look at other ways to provide PDT.
Daylight PDT, which was pioneered by Dr. Haedersdal’s mentor, Hans Christian Wulf, MD, DMSc, PharmD, professor of dermatology at the University of Copenhagen, provides 80%-90% clearance of thin AKs, lower clearance of thick AKs – and is a nearly pain-free procedure because of continuous photoactivation of protoporphyrin IX, with a Visual Analog Scale in the range of 1-3. “Globally, thousands of patients have been treated [with daylight PDT], which is backed up in the literature with more than 150 publications,” she said.
According to Dr. Haedersdal, MAL cream with daylight activation for treatment of AK was approved in Colombia and Mexico in 2013; in Australia, Brazil, and Costa Rica in 2014; and in Chile, Europe, and New Zealand in 2015. “I do hope that one day you will have daylight PDT approved in the United States,” she said.
The suggested protocol for daylight PDT starts by applying a sunscreen with an organic filter. After about 15 minutes, the lesion or lesions are prepared, and MAL is applied with no occlusion. Patients should start their exposure to daylight within 30 minutes of application, remaining outdoors for 2 hours of continuous exposure, either at a dedicated space located on the ground of the hospital or clinic or at their home. After 2 hours, patients wipe off the remaining cream and are advised to stay indoors for the rest of the day.
“Ideal candidates are those who have large skin areas that can be easily exposed to sunlight,” such as the scalp and lower legs, said Dr. Haedersdal, who is also a visiting scientist at the Wellman Center for Photomedicine, Boston. “If patients are treated in areas covered by clothing, it can be greasy and sticky with the cream. In these cases, you can cover the area with Tegaderm, which allows for 99% light transmission. Daylight can shine through and the Tegaderm can be removed after the procedure.”
On rainy days between April 1 and October 1 in Copenhagen, she said, daylight PDT is provided in a greenhouse in the hospital garden, with a heater and blankets for patients when the temperature falls below 10° C.
The amount of light required for a treatment effect is 5,000-10,000 lux, and the number of lux on a sunny day in Denmark is about 100,000, she said. “That means that all year round in countries south of latitude 45 degrees N, patients can be treated with daylight PDT.”
To intensify the treatment efficacy of conventional PDT and daylight PDT, especially in those with severely photodamaged skin, combining treatment with a physical pretreatment technique such as curettage, ablative fractional laser, microdermabrasion, microneedling, and nonablative fractional laser is another strategy. A small randomized controlled trial found that ablative fractional laser treatment extended notable relative effectiveness, compared with other physical enhancement techniques.
Dr. Haedersdal and colleagues published a study that compared pretreatment with ablative fractional laser and microdermabrasion pads before daylight PDT for AKs in field-cancerized skin. They found that with a single treatment, combination therapy with ablative fractional laser before daylight PDT led to significantly greater efficacious AK clearance and skin rejuvenation, compared with treatment with microdermabrasion.
“We don’t know why this is, but we believe it may be due to the fact that with the laser, we have a photothermal response, which in combination with the photochemical response from the photodynamic therapy induces a synergistic effect,” she said.
A range of topical treatments can also be given in combination with PDT. In a meta-analysis of 10 randomized controlled trials, German researchers evaluated the efficacy of PDT combined with imiquimod cream, 5-fluorouracil cream, tazarotene gel, and calcipotriol ointment. They concluded that the combination of PDT with another topical drug intervention improves AK clearance rates, compared with monotherapy.
More recently, the same authors summarized the current knowledge on the efficacy and safety of local combination therapies for the treatment of patients with AK in a review article, which Dr. Haedersdal said provides a nice overview of this topic.
Dr. Haedersdal disclosed that she has received equipment from Cherry Imaging, Cynosure-Hologic, MiraDry, and PerfAction Technologies. She has also received research grants from Leo Pharma, Lutronic, Mirai Medical, Novoxel, and Venus Concept.
.
“We have conventional PDT, daylight PDT; we can combine with a range of topicals, and we can combine a range of different physical treatment procedures in order to provide better and individualized treatment regimens for our patients,” Merete Haedersdal, MD, PhD, DMSc, professor of dermatology at the University of Copenhagen, said during a course on laser and aesthetic skin therapy.
In Europe, PDT consists of a three-step procedure: curettage of AKs, application of photosensitizer on the skin (typically methyl aminolevulinate, versus aminolevulinic acid, used more often in the United States), and illumination with red light (versus blue light, used more often in the United States), which causes a photochemical reaction.
“It’s a photochemical-reaction concept with which we can achieve up to 90% cure rates of AKs at 3 months,” Dr. Haedersdal said during the meeting, which was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine.
PDT is also used in Europe for select patients with Bowen’s disease (yielding a 90% cure rate at 3 months, 70% at 2 years); superficial basal cell carcinoma (yielding a 90% cure rate at 3 months, 75% at 5 years), and nodular BCC (yielding a 90% cure rate at 3 months, 75% at 5 years.
“With conventional PDT, whether it’s blue light, red light, MAL, or ALA, we have beautiful cosmesis, but we also have a challenge, which is pain,” she said. This is behind the motivation to look at other ways to provide PDT.
Daylight PDT, which was pioneered by Dr. Haedersdal’s mentor, Hans Christian Wulf, MD, DMSc, PharmD, professor of dermatology at the University of Copenhagen, provides 80%-90% clearance of thin AKs, lower clearance of thick AKs – and is a nearly pain-free procedure because of continuous photoactivation of protoporphyrin IX, with a Visual Analog Scale in the range of 1-3. “Globally, thousands of patients have been treated [with daylight PDT], which is backed up in the literature with more than 150 publications,” she said.
According to Dr. Haedersdal, MAL cream with daylight activation for treatment of AK was approved in Colombia and Mexico in 2013; in Australia, Brazil, and Costa Rica in 2014; and in Chile, Europe, and New Zealand in 2015. “I do hope that one day you will have daylight PDT approved in the United States,” she said.
The suggested protocol for daylight PDT starts by applying a sunscreen with an organic filter. After about 15 minutes, the lesion or lesions are prepared, and MAL is applied with no occlusion. Patients should start their exposure to daylight within 30 minutes of application, remaining outdoors for 2 hours of continuous exposure, either at a dedicated space located on the ground of the hospital or clinic or at their home. After 2 hours, patients wipe off the remaining cream and are advised to stay indoors for the rest of the day.
“Ideal candidates are those who have large skin areas that can be easily exposed to sunlight,” such as the scalp and lower legs, said Dr. Haedersdal, who is also a visiting scientist at the Wellman Center for Photomedicine, Boston. “If patients are treated in areas covered by clothing, it can be greasy and sticky with the cream. In these cases, you can cover the area with Tegaderm, which allows for 99% light transmission. Daylight can shine through and the Tegaderm can be removed after the procedure.”
On rainy days between April 1 and October 1 in Copenhagen, she said, daylight PDT is provided in a greenhouse in the hospital garden, with a heater and blankets for patients when the temperature falls below 10° C.
The amount of light required for a treatment effect is 5,000-10,000 lux, and the number of lux on a sunny day in Denmark is about 100,000, she said. “That means that all year round in countries south of latitude 45 degrees N, patients can be treated with daylight PDT.”
To intensify the treatment efficacy of conventional PDT and daylight PDT, especially in those with severely photodamaged skin, combining treatment with a physical pretreatment technique such as curettage, ablative fractional laser, microdermabrasion, microneedling, and nonablative fractional laser is another strategy. A small randomized controlled trial found that ablative fractional laser treatment extended notable relative effectiveness, compared with other physical enhancement techniques.
Dr. Haedersdal and colleagues published a study that compared pretreatment with ablative fractional laser and microdermabrasion pads before daylight PDT for AKs in field-cancerized skin. They found that with a single treatment, combination therapy with ablative fractional laser before daylight PDT led to significantly greater efficacious AK clearance and skin rejuvenation, compared with treatment with microdermabrasion.
“We don’t know why this is, but we believe it may be due to the fact that with the laser, we have a photothermal response, which in combination with the photochemical response from the photodynamic therapy induces a synergistic effect,” she said.
A range of topical treatments can also be given in combination with PDT. In a meta-analysis of 10 randomized controlled trials, German researchers evaluated the efficacy of PDT combined with imiquimod cream, 5-fluorouracil cream, tazarotene gel, and calcipotriol ointment. They concluded that the combination of PDT with another topical drug intervention improves AK clearance rates, compared with monotherapy.
More recently, the same authors summarized the current knowledge on the efficacy and safety of local combination therapies for the treatment of patients with AK in a review article, which Dr. Haedersdal said provides a nice overview of this topic.
Dr. Haedersdal disclosed that she has received equipment from Cherry Imaging, Cynosure-Hologic, MiraDry, and PerfAction Technologies. She has also received research grants from Leo Pharma, Lutronic, Mirai Medical, Novoxel, and Venus Concept.
FROM A LASER & AESTHETIC SKIN THERAPY COURSE
FDA issues warning about use of dermal fillers with needle-free devices
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Specifically, the warning advises consumers and health care professionals “not to use needle-free devices such as hyaluron pens for injection of hyaluronic acid (HA) or other lip and facial fillers, collectively and commonly referred to as dermal fillers or fillers.”
According to the statement, the agency “is aware of serious injuries and in some cases, permanent harm to the skin, lips, or eyes with the use of needle-free devices for injection of fillers.”
Needle-free devices and lip and facial fillers for use with these devices are being sold directly to consumers online, and are promoted on social media “to increase lip volume, improve the appearance of wrinkles, change the shape of the nose, and other similar procedures,” according to the FDA warning.
The FDA points out that FDA-approved dermal fillers are for prescription use only, and should be administered only by licensed health care professionals using a syringe with a needle or cannula, and advises consumers not to buy or use lip or facial fillers sold directly to the public.
These products may be contaminated with infectious agents or chemicals. Moreover, “needle-free injection devices for aesthetic purposes do not provide enough control over where the injected product is placed,” the statement adds. In addition to infections, other risks include bleeding and bruising, formation of lumps, allergic reactions, blockage of a blood vessel (which can result in necrosis, blindness, or stroke), and transmission of diseases from sharing devices.
The FDA’s recommendations for health care providers include not using any aesthetic fillers with a needle-free device, and not using approved dermal fillers in such devices.
The American Society for Dermatologic Surgery Association (ASDSA) commended the FDA on the safety communication in a statement issued on October 11. In February, the ASDSA issued an alert about children using hyaluron pens to self-inject hyaluronic filler into the epidermal and upper dermal skin layers.
“I am pleased that the FDA has taken notice of this disturbing new trend, especially that of children using these devices on social media,” ASDSA president Mathew Avram, MD, JD, director of the Dermatology Laser and Cosmetic Center, at Massachusetts General Hospital, Boston, said in the statement. “The complexity of facial anatomy requires in-depth knowledge and expertise, and patients should always have medical procedures done by a physician who also has knowledge of adverse events,” he added, urging consumers to see a board-certified dermatologist before undergoing any cosmetic procedure.
In response to a query, an FDA spokesperson did not have an estimate of the number of reports of these adverse events.
People who have problems or are concerned about having had a filler injected with a needle-free device should contact a licensed health care provider. Consumers and health care professionals should report adverse events related to injection of fillers with a needle-free device to the FDA’s MedWatch program. In addition to MedWatch, adverse events can also be reported to the Cutaneous Procedures Adverse Events Reporting (CAPER) Registry, established earlier this year by the ASDSA with the department of dermatology at Northwestern University, Chicago.
*This story was updated on October 12.
.
Specifically, the warning advises consumers and health care professionals “not to use needle-free devices such as hyaluron pens for injection of hyaluronic acid (HA) or other lip and facial fillers, collectively and commonly referred to as dermal fillers or fillers.”
According to the statement, the agency “is aware of serious injuries and in some cases, permanent harm to the skin, lips, or eyes with the use of needle-free devices for injection of fillers.”
Needle-free devices and lip and facial fillers for use with these devices are being sold directly to consumers online, and are promoted on social media “to increase lip volume, improve the appearance of wrinkles, change the shape of the nose, and other similar procedures,” according to the FDA warning.
The FDA points out that FDA-approved dermal fillers are for prescription use only, and should be administered only by licensed health care professionals using a syringe with a needle or cannula, and advises consumers not to buy or use lip or facial fillers sold directly to the public.
These products may be contaminated with infectious agents or chemicals. Moreover, “needle-free injection devices for aesthetic purposes do not provide enough control over where the injected product is placed,” the statement adds. In addition to infections, other risks include bleeding and bruising, formation of lumps, allergic reactions, blockage of a blood vessel (which can result in necrosis, blindness, or stroke), and transmission of diseases from sharing devices.
The FDA’s recommendations for health care providers include not using any aesthetic fillers with a needle-free device, and not using approved dermal fillers in such devices.
The American Society for Dermatologic Surgery Association (ASDSA) commended the FDA on the safety communication in a statement issued on October 11. In February, the ASDSA issued an alert about children using hyaluron pens to self-inject hyaluronic filler into the epidermal and upper dermal skin layers.
“I am pleased that the FDA has taken notice of this disturbing new trend, especially that of children using these devices on social media,” ASDSA president Mathew Avram, MD, JD, director of the Dermatology Laser and Cosmetic Center, at Massachusetts General Hospital, Boston, said in the statement. “The complexity of facial anatomy requires in-depth knowledge and expertise, and patients should always have medical procedures done by a physician who also has knowledge of adverse events,” he added, urging consumers to see a board-certified dermatologist before undergoing any cosmetic procedure.
In response to a query, an FDA spokesperson did not have an estimate of the number of reports of these adverse events.
People who have problems or are concerned about having had a filler injected with a needle-free device should contact a licensed health care provider. Consumers and health care professionals should report adverse events related to injection of fillers with a needle-free device to the FDA’s MedWatch program. In addition to MedWatch, adverse events can also be reported to the Cutaneous Procedures Adverse Events Reporting (CAPER) Registry, established earlier this year by the ASDSA with the department of dermatology at Northwestern University, Chicago.
*This story was updated on October 12.
.
Specifically, the warning advises consumers and health care professionals “not to use needle-free devices such as hyaluron pens for injection of hyaluronic acid (HA) or other lip and facial fillers, collectively and commonly referred to as dermal fillers or fillers.”
According to the statement, the agency “is aware of serious injuries and in some cases, permanent harm to the skin, lips, or eyes with the use of needle-free devices for injection of fillers.”
Needle-free devices and lip and facial fillers for use with these devices are being sold directly to consumers online, and are promoted on social media “to increase lip volume, improve the appearance of wrinkles, change the shape of the nose, and other similar procedures,” according to the FDA warning.
The FDA points out that FDA-approved dermal fillers are for prescription use only, and should be administered only by licensed health care professionals using a syringe with a needle or cannula, and advises consumers not to buy or use lip or facial fillers sold directly to the public.
These products may be contaminated with infectious agents or chemicals. Moreover, “needle-free injection devices for aesthetic purposes do not provide enough control over where the injected product is placed,” the statement adds. In addition to infections, other risks include bleeding and bruising, formation of lumps, allergic reactions, blockage of a blood vessel (which can result in necrosis, blindness, or stroke), and transmission of diseases from sharing devices.
The FDA’s recommendations for health care providers include not using any aesthetic fillers with a needle-free device, and not using approved dermal fillers in such devices.
The American Society for Dermatologic Surgery Association (ASDSA) commended the FDA on the safety communication in a statement issued on October 11. In February, the ASDSA issued an alert about children using hyaluron pens to self-inject hyaluronic filler into the epidermal and upper dermal skin layers.
“I am pleased that the FDA has taken notice of this disturbing new trend, especially that of children using these devices on social media,” ASDSA president Mathew Avram, MD, JD, director of the Dermatology Laser and Cosmetic Center, at Massachusetts General Hospital, Boston, said in the statement. “The complexity of facial anatomy requires in-depth knowledge and expertise, and patients should always have medical procedures done by a physician who also has knowledge of adverse events,” he added, urging consumers to see a board-certified dermatologist before undergoing any cosmetic procedure.
In response to a query, an FDA spokesperson did not have an estimate of the number of reports of these adverse events.
People who have problems or are concerned about having had a filler injected with a needle-free device should contact a licensed health care provider. Consumers and health care professionals should report adverse events related to injection of fillers with a needle-free device to the FDA’s MedWatch program. In addition to MedWatch, adverse events can also be reported to the Cutaneous Procedures Adverse Events Reporting (CAPER) Registry, established earlier this year by the ASDSA with the department of dermatology at Northwestern University, Chicago.
*This story was updated on October 12.
In atopic dermatitis trial, abrocitinib offers faster itch relief than dupilumab
), in a multicenter randomized trial presented as a late breaker at the annual meeting of the European Academy of Dermatology and Venereology.
The earlier onset of action with the JAK inhibitor was achieved even though most patients in both arms were on topical corticosteroids, a design element that “is clinically relevant” for a practical comparison of these two agents, according to Kristian Reich, MD, PhD, Center for Translational Research in Inflammatory Skin Diseases, University Medical Center, Hamburg-Eppendorf, Germany.
The goal of this phase 3b trial, called JADE DARE, was to compare relative safety and efficacy of these strategies over the early course of treatment, he said.
Over 700 patients randomized
JADE DARE enrolled 727 patients over age 18 years who previously had an inadequate response to conventional topical therapies. All had moderate to severe AD defined by criteria such as body surface area greater than or equal to 10% and Eczema Area Severity Index (EASI) greater than or equal to 16. They were randomly assigned to 200 mg oral abrocitinib once daily or 300 mg subcutaneous dupilumab (after a loading dose of 600 mg) every 2 weeks. A double-dummy design preserved blinding.
The coprimary endpoints were at least a 4-point improvement in pruritus as measured with the Peak Pruritus Numerical Rating Scale (PP-NRS) score at week 2 and at least a 90% improvement in the EASI (EASI 90) at week 4.
The primary endpoint for pruritus at 2 weeks was reached by nearly twice as many patients randomly assigned to abrocitinib (46.2% vs. 25.5%; P < .001). The proportion of those meeting the EASI 90 endpoint at week 4 was also superior on abrocitinib (28.5% vs. 14.6%; P < .001)
Advantage for pruritus control dissipates
For the pruritus endpoint, the advantage of abrocitinib slowly diminished over time after the peak difference observed at 2 weeks. Although the advantage at week 4 (58.1% vs. 40.8%) and week 8 (65.8% vs. 52.7%) remained sizable, there were very small differences thereafter. However, Dr. Reich pointed out that the percentages continued to favor abrocitinib at least numerically through the 26 weeks of follow-up completed so far.
The pattern of response on EASI 90 was not the same. After demonstrating superiority at the 4-week timepoint, the advantage of abrocitinib persisted. When compared at week 16, which was a secondary endpoint of the JADE DARE trial, the advantage of abrocitinib remained significant (54.3% vs. 41.9%; P < .001). The advantage of abrocitinib narrowed but remained numerically superior at 26 weeks (54.6% vs. 47.6%).
Based on the data collected to date, “abrocitinib is clearly superior early on,” Dr. Reich said. Moreover, he reiterated that topical corticosteroids were allowed as background therapy in both arms.
“It is difficult to show an advantage for one active therapy over the other in patients on background corticosteroids,” Dr. Reich maintained.
Both drugs are well tolerated
The drugs were similarly well tolerated. Serious adverse events were uncommon in either arm. The rate of study dropouts due to an adverse event potentially related to treatment assignment was 3% in each group.
Nausea (19% vs. 2%), acne (13.5% vs. 2%), and headache (13% vs. 7.5%) were all more common in patients randomly assigned to abrocitinib. Conjunctivitis was more common in the group randomly assigned to dupilumab (10% vs. 2%).
The two deaths that occurred during this study were in the abrocitinib arm, but one was the result of COVID-19 infection and the other was a cardiovascular event in a patient with risk factors. Neither was considered to be treatment-related.
Abrocitinib’s relative selectivity for the JAK1 inhibitor is a potential differentiator from other currently available JAK inhibitors, although direct comparisons of these therapies for clinical activity in AD as well as most other diseases remains limited.
The relatively rapid relief of pruritus with the JAK inhibitor relative to the monoclonal antibody in the JADE DARE trial is likely to be perceived as clinically significant by patients with AD, according to Sonja Ständer, MD, professor of dermatology and neurodermatology at the University Hospital Münster, Germany.
“One of the highest needs of patients with atopic dermatitis is a rapid and profound relief of itch,” Dr. Ständer, who wrote a review article on AD earlier this year, said in an interview.
Although several current therapies are effective against pruritus, Dr. Ständer believes that the higher proportion of patients achieving itch control at 2 weeks on abrocitinib “will attract the attention of affected patients.”
However, she added that patients need to take both benefits and risks into account, indicating that clinical utility cannot be judged on a single outcome. In selecting one drug over the others, she advised “a balanced use of therapies.”
Abrocitinib was first approved in the United Kingdom in early September, followed by Japan last Thursday, for the treatment of moderate to severe AD in patients ages 12 and older. It is under review elsewhere, including in the United States and the European Union for AD.
In September, the FDA approved the first JAK inhibitor for treating AD – a topical JAK inhibitor, ruxolitinib.
Dr. Reich reports financial relationships with 20 pharmaceutical companies, including Pfizer, which provided funding for the JADE DARE trial. Dr. Ständer reports financial relationships with Beiersdorf AG, Galderma, Kliniska, Lilly, Pfizer, and Sanofi.
A version of this article first appeared on Medscape.com.
), in a multicenter randomized trial presented as a late breaker at the annual meeting of the European Academy of Dermatology and Venereology.
The earlier onset of action with the JAK inhibitor was achieved even though most patients in both arms were on topical corticosteroids, a design element that “is clinically relevant” for a practical comparison of these two agents, according to Kristian Reich, MD, PhD, Center for Translational Research in Inflammatory Skin Diseases, University Medical Center, Hamburg-Eppendorf, Germany.
The goal of this phase 3b trial, called JADE DARE, was to compare relative safety and efficacy of these strategies over the early course of treatment, he said.
Over 700 patients randomized
JADE DARE enrolled 727 patients over age 18 years who previously had an inadequate response to conventional topical therapies. All had moderate to severe AD defined by criteria such as body surface area greater than or equal to 10% and Eczema Area Severity Index (EASI) greater than or equal to 16. They were randomly assigned to 200 mg oral abrocitinib once daily or 300 mg subcutaneous dupilumab (after a loading dose of 600 mg) every 2 weeks. A double-dummy design preserved blinding.
The coprimary endpoints were at least a 4-point improvement in pruritus as measured with the Peak Pruritus Numerical Rating Scale (PP-NRS) score at week 2 and at least a 90% improvement in the EASI (EASI 90) at week 4.
The primary endpoint for pruritus at 2 weeks was reached by nearly twice as many patients randomly assigned to abrocitinib (46.2% vs. 25.5%; P < .001). The proportion of those meeting the EASI 90 endpoint at week 4 was also superior on abrocitinib (28.5% vs. 14.6%; P < .001)
Advantage for pruritus control dissipates
For the pruritus endpoint, the advantage of abrocitinib slowly diminished over time after the peak difference observed at 2 weeks. Although the advantage at week 4 (58.1% vs. 40.8%) and week 8 (65.8% vs. 52.7%) remained sizable, there were very small differences thereafter. However, Dr. Reich pointed out that the percentages continued to favor abrocitinib at least numerically through the 26 weeks of follow-up completed so far.
The pattern of response on EASI 90 was not the same. After demonstrating superiority at the 4-week timepoint, the advantage of abrocitinib persisted. When compared at week 16, which was a secondary endpoint of the JADE DARE trial, the advantage of abrocitinib remained significant (54.3% vs. 41.9%; P < .001). The advantage of abrocitinib narrowed but remained numerically superior at 26 weeks (54.6% vs. 47.6%).
Based on the data collected to date, “abrocitinib is clearly superior early on,” Dr. Reich said. Moreover, he reiterated that topical corticosteroids were allowed as background therapy in both arms.
“It is difficult to show an advantage for one active therapy over the other in patients on background corticosteroids,” Dr. Reich maintained.
Both drugs are well tolerated
The drugs were similarly well tolerated. Serious adverse events were uncommon in either arm. The rate of study dropouts due to an adverse event potentially related to treatment assignment was 3% in each group.
Nausea (19% vs. 2%), acne (13.5% vs. 2%), and headache (13% vs. 7.5%) were all more common in patients randomly assigned to abrocitinib. Conjunctivitis was more common in the group randomly assigned to dupilumab (10% vs. 2%).
The two deaths that occurred during this study were in the abrocitinib arm, but one was the result of COVID-19 infection and the other was a cardiovascular event in a patient with risk factors. Neither was considered to be treatment-related.
Abrocitinib’s relative selectivity for the JAK1 inhibitor is a potential differentiator from other currently available JAK inhibitors, although direct comparisons of these therapies for clinical activity in AD as well as most other diseases remains limited.
The relatively rapid relief of pruritus with the JAK inhibitor relative to the monoclonal antibody in the JADE DARE trial is likely to be perceived as clinically significant by patients with AD, according to Sonja Ständer, MD, professor of dermatology and neurodermatology at the University Hospital Münster, Germany.
“One of the highest needs of patients with atopic dermatitis is a rapid and profound relief of itch,” Dr. Ständer, who wrote a review article on AD earlier this year, said in an interview.
Although several current therapies are effective against pruritus, Dr. Ständer believes that the higher proportion of patients achieving itch control at 2 weeks on abrocitinib “will attract the attention of affected patients.”
However, she added that patients need to take both benefits and risks into account, indicating that clinical utility cannot be judged on a single outcome. In selecting one drug over the others, she advised “a balanced use of therapies.”
Abrocitinib was first approved in the United Kingdom in early September, followed by Japan last Thursday, for the treatment of moderate to severe AD in patients ages 12 and older. It is under review elsewhere, including in the United States and the European Union for AD.
In September, the FDA approved the first JAK inhibitor for treating AD – a topical JAK inhibitor, ruxolitinib.
Dr. Reich reports financial relationships with 20 pharmaceutical companies, including Pfizer, which provided funding for the JADE DARE trial. Dr. Ständer reports financial relationships with Beiersdorf AG, Galderma, Kliniska, Lilly, Pfizer, and Sanofi.
A version of this article first appeared on Medscape.com.
), in a multicenter randomized trial presented as a late breaker at the annual meeting of the European Academy of Dermatology and Venereology.
The earlier onset of action with the JAK inhibitor was achieved even though most patients in both arms were on topical corticosteroids, a design element that “is clinically relevant” for a practical comparison of these two agents, according to Kristian Reich, MD, PhD, Center for Translational Research in Inflammatory Skin Diseases, University Medical Center, Hamburg-Eppendorf, Germany.
The goal of this phase 3b trial, called JADE DARE, was to compare relative safety and efficacy of these strategies over the early course of treatment, he said.
Over 700 patients randomized
JADE DARE enrolled 727 patients over age 18 years who previously had an inadequate response to conventional topical therapies. All had moderate to severe AD defined by criteria such as body surface area greater than or equal to 10% and Eczema Area Severity Index (EASI) greater than or equal to 16. They were randomly assigned to 200 mg oral abrocitinib once daily or 300 mg subcutaneous dupilumab (after a loading dose of 600 mg) every 2 weeks. A double-dummy design preserved blinding.
The coprimary endpoints were at least a 4-point improvement in pruritus as measured with the Peak Pruritus Numerical Rating Scale (PP-NRS) score at week 2 and at least a 90% improvement in the EASI (EASI 90) at week 4.
The primary endpoint for pruritus at 2 weeks was reached by nearly twice as many patients randomly assigned to abrocitinib (46.2% vs. 25.5%; P < .001). The proportion of those meeting the EASI 90 endpoint at week 4 was also superior on abrocitinib (28.5% vs. 14.6%; P < .001)
Advantage for pruritus control dissipates
For the pruritus endpoint, the advantage of abrocitinib slowly diminished over time after the peak difference observed at 2 weeks. Although the advantage at week 4 (58.1% vs. 40.8%) and week 8 (65.8% vs. 52.7%) remained sizable, there were very small differences thereafter. However, Dr. Reich pointed out that the percentages continued to favor abrocitinib at least numerically through the 26 weeks of follow-up completed so far.
The pattern of response on EASI 90 was not the same. After demonstrating superiority at the 4-week timepoint, the advantage of abrocitinib persisted. When compared at week 16, which was a secondary endpoint of the JADE DARE trial, the advantage of abrocitinib remained significant (54.3% vs. 41.9%; P < .001). The advantage of abrocitinib narrowed but remained numerically superior at 26 weeks (54.6% vs. 47.6%).
Based on the data collected to date, “abrocitinib is clearly superior early on,” Dr. Reich said. Moreover, he reiterated that topical corticosteroids were allowed as background therapy in both arms.
“It is difficult to show an advantage for one active therapy over the other in patients on background corticosteroids,” Dr. Reich maintained.
Both drugs are well tolerated
The drugs were similarly well tolerated. Serious adverse events were uncommon in either arm. The rate of study dropouts due to an adverse event potentially related to treatment assignment was 3% in each group.
Nausea (19% vs. 2%), acne (13.5% vs. 2%), and headache (13% vs. 7.5%) were all more common in patients randomly assigned to abrocitinib. Conjunctivitis was more common in the group randomly assigned to dupilumab (10% vs. 2%).
The two deaths that occurred during this study were in the abrocitinib arm, but one was the result of COVID-19 infection and the other was a cardiovascular event in a patient with risk factors. Neither was considered to be treatment-related.
Abrocitinib’s relative selectivity for the JAK1 inhibitor is a potential differentiator from other currently available JAK inhibitors, although direct comparisons of these therapies for clinical activity in AD as well as most other diseases remains limited.
The relatively rapid relief of pruritus with the JAK inhibitor relative to the monoclonal antibody in the JADE DARE trial is likely to be perceived as clinically significant by patients with AD, according to Sonja Ständer, MD, professor of dermatology and neurodermatology at the University Hospital Münster, Germany.
“One of the highest needs of patients with atopic dermatitis is a rapid and profound relief of itch,” Dr. Ständer, who wrote a review article on AD earlier this year, said in an interview.
Although several current therapies are effective against pruritus, Dr. Ständer believes that the higher proportion of patients achieving itch control at 2 weeks on abrocitinib “will attract the attention of affected patients.”
However, she added that patients need to take both benefits and risks into account, indicating that clinical utility cannot be judged on a single outcome. In selecting one drug over the others, she advised “a balanced use of therapies.”
Abrocitinib was first approved in the United Kingdom in early September, followed by Japan last Thursday, for the treatment of moderate to severe AD in patients ages 12 and older. It is under review elsewhere, including in the United States and the European Union for AD.
In September, the FDA approved the first JAK inhibitor for treating AD – a topical JAK inhibitor, ruxolitinib.
Dr. Reich reports financial relationships with 20 pharmaceutical companies, including Pfizer, which provided funding for the JADE DARE trial. Dr. Ständer reports financial relationships with Beiersdorf AG, Galderma, Kliniska, Lilly, Pfizer, and Sanofi.
A version of this article first appeared on Medscape.com.