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NIH to study COVID vaccine booster in people with autoimmune disease
In the wake of the Centers for Disease Control and Prevention’s recommendation for a third COVID-19 mRNA vaccine dose for immunocompromised people and the Food and Drug Administration’s authorization of the third dose, the according to an announcement.
The investigators of the trial, called COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders, also want to determine if pausing immunosuppressive therapy for autoimmune disease improves the antibody response to an extra dose of a COVID-19 vaccine.
The trial will specifically look at the effects of mycophenolate mofetil (MMF) or mycophenolic acid (MPA), and methotrexate (MTX), or receipt of B cell–depletion therapy such as rituximab within the past 12 months on immune response to a booster dose in people with systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, or pemphigus. They have to have either no serologic response to their initial COVID-19 vaccine regimen or a suboptimal response, defined as a Roche Elecsys Anti-SARS-CoV-2 S (RBD) result greater than or equal to 50 U/mL.
The results of studies conducted in solid-organ transplant recipients who take immunosuppressants showed that an extra dose of vaccine could improve the immune response to the vaccine in many of the individuals, which suggests that the same approach might work in people with autoimmune disease who need treatment with immunosuppressive drugs. Improving the immune response of people with autoimmune disease to COVID-19 vaccines is important because higher rates of severe COVID-19 and death have been reported in this group of patients than in the general population, and it is unclear whether this is attributable to the autoimmune disease, the immunosuppressive medications taken to treat it, or both.
The open-label trial, conducted by the NIAID-funded Autoimmunity Centers of Excellence, aims to enroll 600 people aged 18 years and older with those conditions at 15-20 sites in the United States.
Because medications commonly taken by people with these conditions have been associated with poorer immune responses to vaccines, the trial will randomize the following two cohorts to stop or continue taking their immunosuppressive medication(s) or stop them before and after the booster according to protocol:
- Cohort 1 includes people who are taking MMF or MPA, without additional B cell–depleting medications or MTX.
- Cohort 2 includes people who are taking MTX without additional B cell–depleting medications or MMF/MPA.
A third, nonrandomized cohort consists of people who have received B cell–depletion therapy within the past 12 months regardless of whether they are also taking MMF/MPA or MTX.
Besides the cohort-specific exclusions, other rheumatic disease medications, including biologics, are allowed in the groups.
The primary outcome of the trial is the proportion of participants who have a protective antibody response at week 4. Secondary outcomes will examine various antibody responses at intervals, changes in disease activity across autoimmune diseases, adverse events, and SARS-CoV-2 infections out to 48 weeks.
Study participants will be followed for a total of 13 months. Preliminary results are expected in November 2021, according to the National Institutes of Health.
The trial is being led by Judith James, MD, PhD; Meggan Mackay, MD, MS; Dinesh Khanna, MBBS, MSc; and Amit Bar-Or, MD.
In the wake of the Centers for Disease Control and Prevention’s recommendation for a third COVID-19 mRNA vaccine dose for immunocompromised people and the Food and Drug Administration’s authorization of the third dose, the according to an announcement.
The investigators of the trial, called COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders, also want to determine if pausing immunosuppressive therapy for autoimmune disease improves the antibody response to an extra dose of a COVID-19 vaccine.
The trial will specifically look at the effects of mycophenolate mofetil (MMF) or mycophenolic acid (MPA), and methotrexate (MTX), or receipt of B cell–depletion therapy such as rituximab within the past 12 months on immune response to a booster dose in people with systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, or pemphigus. They have to have either no serologic response to their initial COVID-19 vaccine regimen or a suboptimal response, defined as a Roche Elecsys Anti-SARS-CoV-2 S (RBD) result greater than or equal to 50 U/mL.
The results of studies conducted in solid-organ transplant recipients who take immunosuppressants showed that an extra dose of vaccine could improve the immune response to the vaccine in many of the individuals, which suggests that the same approach might work in people with autoimmune disease who need treatment with immunosuppressive drugs. Improving the immune response of people with autoimmune disease to COVID-19 vaccines is important because higher rates of severe COVID-19 and death have been reported in this group of patients than in the general population, and it is unclear whether this is attributable to the autoimmune disease, the immunosuppressive medications taken to treat it, or both.
The open-label trial, conducted by the NIAID-funded Autoimmunity Centers of Excellence, aims to enroll 600 people aged 18 years and older with those conditions at 15-20 sites in the United States.
Because medications commonly taken by people with these conditions have been associated with poorer immune responses to vaccines, the trial will randomize the following two cohorts to stop or continue taking their immunosuppressive medication(s) or stop them before and after the booster according to protocol:
- Cohort 1 includes people who are taking MMF or MPA, without additional B cell–depleting medications or MTX.
- Cohort 2 includes people who are taking MTX without additional B cell–depleting medications or MMF/MPA.
A third, nonrandomized cohort consists of people who have received B cell–depletion therapy within the past 12 months regardless of whether they are also taking MMF/MPA or MTX.
Besides the cohort-specific exclusions, other rheumatic disease medications, including biologics, are allowed in the groups.
The primary outcome of the trial is the proportion of participants who have a protective antibody response at week 4. Secondary outcomes will examine various antibody responses at intervals, changes in disease activity across autoimmune diseases, adverse events, and SARS-CoV-2 infections out to 48 weeks.
Study participants will be followed for a total of 13 months. Preliminary results are expected in November 2021, according to the National Institutes of Health.
The trial is being led by Judith James, MD, PhD; Meggan Mackay, MD, MS; Dinesh Khanna, MBBS, MSc; and Amit Bar-Or, MD.
In the wake of the Centers for Disease Control and Prevention’s recommendation for a third COVID-19 mRNA vaccine dose for immunocompromised people and the Food and Drug Administration’s authorization of the third dose, the according to an announcement.
The investigators of the trial, called COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders, also want to determine if pausing immunosuppressive therapy for autoimmune disease improves the antibody response to an extra dose of a COVID-19 vaccine.
The trial will specifically look at the effects of mycophenolate mofetil (MMF) or mycophenolic acid (MPA), and methotrexate (MTX), or receipt of B cell–depletion therapy such as rituximab within the past 12 months on immune response to a booster dose in people with systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, or pemphigus. They have to have either no serologic response to their initial COVID-19 vaccine regimen or a suboptimal response, defined as a Roche Elecsys Anti-SARS-CoV-2 S (RBD) result greater than or equal to 50 U/mL.
The results of studies conducted in solid-organ transplant recipients who take immunosuppressants showed that an extra dose of vaccine could improve the immune response to the vaccine in many of the individuals, which suggests that the same approach might work in people with autoimmune disease who need treatment with immunosuppressive drugs. Improving the immune response of people with autoimmune disease to COVID-19 vaccines is important because higher rates of severe COVID-19 and death have been reported in this group of patients than in the general population, and it is unclear whether this is attributable to the autoimmune disease, the immunosuppressive medications taken to treat it, or both.
The open-label trial, conducted by the NIAID-funded Autoimmunity Centers of Excellence, aims to enroll 600 people aged 18 years and older with those conditions at 15-20 sites in the United States.
Because medications commonly taken by people with these conditions have been associated with poorer immune responses to vaccines, the trial will randomize the following two cohorts to stop or continue taking their immunosuppressive medication(s) or stop them before and after the booster according to protocol:
- Cohort 1 includes people who are taking MMF or MPA, without additional B cell–depleting medications or MTX.
- Cohort 2 includes people who are taking MTX without additional B cell–depleting medications or MMF/MPA.
A third, nonrandomized cohort consists of people who have received B cell–depletion therapy within the past 12 months regardless of whether they are also taking MMF/MPA or MTX.
Besides the cohort-specific exclusions, other rheumatic disease medications, including biologics, are allowed in the groups.
The primary outcome of the trial is the proportion of participants who have a protective antibody response at week 4. Secondary outcomes will examine various antibody responses at intervals, changes in disease activity across autoimmune diseases, adverse events, and SARS-CoV-2 infections out to 48 weeks.
Study participants will be followed for a total of 13 months. Preliminary results are expected in November 2021, according to the National Institutes of Health.
The trial is being led by Judith James, MD, PhD; Meggan Mackay, MD, MS; Dinesh Khanna, MBBS, MSc; and Amit Bar-Or, MD.
FDA okays difelikefalin for dialysis-associated pruritus in patients with CKD
Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.
“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.
Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
Two pivotal trials with fewer than 900 total randomized patients
The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.
Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.
In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.
The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.
In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.
Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
What will it cost, and will it be covered?
The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.
Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.
Other nephrologists have a more positive take on the existing treatment options.
“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.
“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
Adverse-event profiles
In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.
An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”
Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.
“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”
Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.
The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.
The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.
Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.
“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.
Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
Two pivotal trials with fewer than 900 total randomized patients
The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.
Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.
In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.
The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.
In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.
Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
What will it cost, and will it be covered?
The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.
Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.
Other nephrologists have a more positive take on the existing treatment options.
“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.
“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
Adverse-event profiles
In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.
An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”
Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.
“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”
Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.
The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.
The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.
Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.
“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.
Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
Two pivotal trials with fewer than 900 total randomized patients
The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.
Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.
In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.
The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.
In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.
Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
What will it cost, and will it be covered?
The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.
Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.
Other nephrologists have a more positive take on the existing treatment options.
“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.
“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
Adverse-event profiles
In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.
An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”
Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.
“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”
Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.
The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.
The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.
Arm and neck rash
The manifestation of what appeared to be an exaggerated sunburn with associated pruritis and blistering (made worse after sun exposure), along with the recent initiation of HCTZ, led to the diagnosis of a phototoxic drug reaction.
There are 2 principal mechanisms of photosensitive drug reactions, phototoxic and photoallergic. Phototoxic reactions occur when the drug absorbs UVA light, causing a chemical reaction that produces either free radicals or stable photoproducts, both of which can cause DNA and tissue damage. This mechanism is more common; the time of onset between exposure and reaction is minutes to hours (as seen with this patient), and the reaction manifests with an exaggerated sunburn appearance.1
Photoallergic reactions typically occur by a delayed-immune response, mediated by photoallergic-specific T-cells reacting to photohaptens. This mechanism is less common, and the time of onset is greater than 24 hours. Photoallergic reactions often present as an eczematous dermatitis and can involve regions not directly exposed to sun.
In this case, the presumed offending agent—HCTZ—was discontinued, and the patient was advised to take sun-protective measures and use topical emollients, cool compresses, and oral analgesics for his acute symptoms. Photoallergic reactions look less like a discrete sunburn and can be treated symptomatically with topical or oral steroids. In addition, the implicated medication should be discontinued.
Text courtesy of Amanda Yaney, MD, and Daniel Stulberg, MD, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque. Image courtesy of Daniel Stulberg, MD.
Lozzi F, Di Raimondo C, Lanna C, et al. Latest evidence regarding the effects of photosensitive drugs on the skin: pathogenic mechanisms and clinical manifestations. Pharmaceutics 2020;12:1104. doi: 10.3390/pharmaceutics12111104
The manifestation of what appeared to be an exaggerated sunburn with associated pruritis and blistering (made worse after sun exposure), along with the recent initiation of HCTZ, led to the diagnosis of a phototoxic drug reaction.
There are 2 principal mechanisms of photosensitive drug reactions, phototoxic and photoallergic. Phototoxic reactions occur when the drug absorbs UVA light, causing a chemical reaction that produces either free radicals or stable photoproducts, both of which can cause DNA and tissue damage. This mechanism is more common; the time of onset between exposure and reaction is minutes to hours (as seen with this patient), and the reaction manifests with an exaggerated sunburn appearance.1
Photoallergic reactions typically occur by a delayed-immune response, mediated by photoallergic-specific T-cells reacting to photohaptens. This mechanism is less common, and the time of onset is greater than 24 hours. Photoallergic reactions often present as an eczematous dermatitis and can involve regions not directly exposed to sun.
In this case, the presumed offending agent—HCTZ—was discontinued, and the patient was advised to take sun-protective measures and use topical emollients, cool compresses, and oral analgesics for his acute symptoms. Photoallergic reactions look less like a discrete sunburn and can be treated symptomatically with topical or oral steroids. In addition, the implicated medication should be discontinued.
Text courtesy of Amanda Yaney, MD, and Daniel Stulberg, MD, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque. Image courtesy of Daniel Stulberg, MD.
The manifestation of what appeared to be an exaggerated sunburn with associated pruritis and blistering (made worse after sun exposure), along with the recent initiation of HCTZ, led to the diagnosis of a phototoxic drug reaction.
There are 2 principal mechanisms of photosensitive drug reactions, phototoxic and photoallergic. Phototoxic reactions occur when the drug absorbs UVA light, causing a chemical reaction that produces either free radicals or stable photoproducts, both of which can cause DNA and tissue damage. This mechanism is more common; the time of onset between exposure and reaction is minutes to hours (as seen with this patient), and the reaction manifests with an exaggerated sunburn appearance.1
Photoallergic reactions typically occur by a delayed-immune response, mediated by photoallergic-specific T-cells reacting to photohaptens. This mechanism is less common, and the time of onset is greater than 24 hours. Photoallergic reactions often present as an eczematous dermatitis and can involve regions not directly exposed to sun.
In this case, the presumed offending agent—HCTZ—was discontinued, and the patient was advised to take sun-protective measures and use topical emollients, cool compresses, and oral analgesics for his acute symptoms. Photoallergic reactions look less like a discrete sunburn and can be treated symptomatically with topical or oral steroids. In addition, the implicated medication should be discontinued.
Text courtesy of Amanda Yaney, MD, and Daniel Stulberg, MD, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque. Image courtesy of Daniel Stulberg, MD.
Lozzi F, Di Raimondo C, Lanna C, et al. Latest evidence regarding the effects of photosensitive drugs on the skin: pathogenic mechanisms and clinical manifestations. Pharmaceutics 2020;12:1104. doi: 10.3390/pharmaceutics12111104
Lozzi F, Di Raimondo C, Lanna C, et al. Latest evidence regarding the effects of photosensitive drugs on the skin: pathogenic mechanisms and clinical manifestations. Pharmaceutics 2020;12:1104. doi: 10.3390/pharmaceutics12111104
Bimekizumab approved in Europe for psoriasis treatment
, according to a statement from the manufacturer.
Bimekizumab (Bimzelx), a humanized IgG1 monoclonal antibody, is the first approved treatment for moderate to severe plaque psoriasis that selectively inhibits interleukin (IL)–17A and IL-17F, the statement from UCB said.
In the United States, the Food and Drug Administration is expected to make a decision on approval of bimekizumab for treating psoriasis on Oct. 15.
Approval in the EU was based on data from three phase 3 trials including a total of 1,480 adult patients with moderate to severe psoriasis, which found that those treated with bimekizumab experienced significantly greater skin clearance, compared with placebo, ustekinumab, and adalimumab, with a favorable safety profile, according to the company.
In all three studies (BE VIVID, BE READY, and BE SURE), more than 80% of patients treated with bimekizumab showed improved skin clearance after 16 weeks, significantly more than those treated with ustekinumab, placebo, or adalimumab, based on an improvement of at least 90% in the Psoriasis Area & Severity Index (PASI 90) and an Investigator’s Global Assessment (IGA) response of clear or almost clear skin (IGA 0/1). In all three studies, these clinical responses persisted after 1 year.
The recommended dose of bimekizumab is 320 mg, given in two subcutaneous injections every 4 weeks to week 16, then every 8 weeks. However, for “some patients” weighing 120 kg or more who have not achieved complete skin clearance at 16 weeks, 320 mg every 4 weeks after that time may improve response to treatment, according to the company statement.
The most common treatment-related adverse events in the studies were upper respiratory tract infections (a majority of which were nasopharyngitis), reported by 14.5% of patients, followed by oral candidiasis, reported by 7.3%.
Results of BE READY and BE VIVID were published in The Lancet. Results of the BE SURE study were published in The New England Journal of Medicine.
Bimekizumab is contraindicated for individuals with clinically important active infections such as tuberculosis, and for individuals with any hypersensitivity to the active substance. More details on bimekizumab are available on the website of the European Medicines Agency.
, according to a statement from the manufacturer.
Bimekizumab (Bimzelx), a humanized IgG1 monoclonal antibody, is the first approved treatment for moderate to severe plaque psoriasis that selectively inhibits interleukin (IL)–17A and IL-17F, the statement from UCB said.
In the United States, the Food and Drug Administration is expected to make a decision on approval of bimekizumab for treating psoriasis on Oct. 15.
Approval in the EU was based on data from three phase 3 trials including a total of 1,480 adult patients with moderate to severe psoriasis, which found that those treated with bimekizumab experienced significantly greater skin clearance, compared with placebo, ustekinumab, and adalimumab, with a favorable safety profile, according to the company.
In all three studies (BE VIVID, BE READY, and BE SURE), more than 80% of patients treated with bimekizumab showed improved skin clearance after 16 weeks, significantly more than those treated with ustekinumab, placebo, or adalimumab, based on an improvement of at least 90% in the Psoriasis Area & Severity Index (PASI 90) and an Investigator’s Global Assessment (IGA) response of clear or almost clear skin (IGA 0/1). In all three studies, these clinical responses persisted after 1 year.
The recommended dose of bimekizumab is 320 mg, given in two subcutaneous injections every 4 weeks to week 16, then every 8 weeks. However, for “some patients” weighing 120 kg or more who have not achieved complete skin clearance at 16 weeks, 320 mg every 4 weeks after that time may improve response to treatment, according to the company statement.
The most common treatment-related adverse events in the studies were upper respiratory tract infections (a majority of which were nasopharyngitis), reported by 14.5% of patients, followed by oral candidiasis, reported by 7.3%.
Results of BE READY and BE VIVID were published in The Lancet. Results of the BE SURE study were published in The New England Journal of Medicine.
Bimekizumab is contraindicated for individuals with clinically important active infections such as tuberculosis, and for individuals with any hypersensitivity to the active substance. More details on bimekizumab are available on the website of the European Medicines Agency.
, according to a statement from the manufacturer.
Bimekizumab (Bimzelx), a humanized IgG1 monoclonal antibody, is the first approved treatment for moderate to severe plaque psoriasis that selectively inhibits interleukin (IL)–17A and IL-17F, the statement from UCB said.
In the United States, the Food and Drug Administration is expected to make a decision on approval of bimekizumab for treating psoriasis on Oct. 15.
Approval in the EU was based on data from three phase 3 trials including a total of 1,480 adult patients with moderate to severe psoriasis, which found that those treated with bimekizumab experienced significantly greater skin clearance, compared with placebo, ustekinumab, and adalimumab, with a favorable safety profile, according to the company.
In all three studies (BE VIVID, BE READY, and BE SURE), more than 80% of patients treated with bimekizumab showed improved skin clearance after 16 weeks, significantly more than those treated with ustekinumab, placebo, or adalimumab, based on an improvement of at least 90% in the Psoriasis Area & Severity Index (PASI 90) and an Investigator’s Global Assessment (IGA) response of clear or almost clear skin (IGA 0/1). In all three studies, these clinical responses persisted after 1 year.
The recommended dose of bimekizumab is 320 mg, given in two subcutaneous injections every 4 weeks to week 16, then every 8 weeks. However, for “some patients” weighing 120 kg or more who have not achieved complete skin clearance at 16 weeks, 320 mg every 4 weeks after that time may improve response to treatment, according to the company statement.
The most common treatment-related adverse events in the studies were upper respiratory tract infections (a majority of which were nasopharyngitis), reported by 14.5% of patients, followed by oral candidiasis, reported by 7.3%.
Results of BE READY and BE VIVID were published in The Lancet. Results of the BE SURE study were published in The New England Journal of Medicine.
Bimekizumab is contraindicated for individuals with clinically important active infections such as tuberculosis, and for individuals with any hypersensitivity to the active substance. More details on bimekizumab are available on the website of the European Medicines Agency.
Annular lesions
This patient was given a diagnosis of disseminated granuloma annulare (DGA). While granuloma annulare usually manifests as a single lesion with a raised erythematous border (often with central pallor or hypopigmentation) it can also manifest as multiple large annular lesions on the extremities and occasionally the trunk, as was seen with this case of DGA.
Although the etiology of DGA is unknown, infections including HIV and hepatitis have been reported as possible triggers. Laboratory testing should be considered if the history or physical examination raises suspicion for either condition. Diabetes has also been associated with the disseminated form and the literature suggests a connection with autoimmune diseases of the liver and thyroid.1
Watchful waiting is usually the best treatment for localized disease, which can spontaneously regress within a year and is usually asymptomatic. Intralesional steroid injections into the raised annulus are more effective than topical steroids, as the effects of the topical steroids are sometimes augmented by occlusion.
Multiple treatments have been proposed for DGA, including UVA treatments, systemic retinoids, doxycycline, and hydroxychloroquine.1 Unfortunately, the disseminated form can persist for many years—even with treatment.
Due to the extent of the lesions, the patient in this case was not interested in intralesional steroid injections, and she had already tried topical steroids. She was prescribed topical tacrolimus to reduce the highly visible nature of her lesions.
Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.
Beretta-Piccoli BT, Mainetti C, Peeters MA, et al. Cutaneous granulomatosis: a comprehensive review. Clin Rev Allergy Immunol. 2018;54:131-146. doi: 10.1007/s12016-017-8666-8
This patient was given a diagnosis of disseminated granuloma annulare (DGA). While granuloma annulare usually manifests as a single lesion with a raised erythematous border (often with central pallor or hypopigmentation) it can also manifest as multiple large annular lesions on the extremities and occasionally the trunk, as was seen with this case of DGA.
Although the etiology of DGA is unknown, infections including HIV and hepatitis have been reported as possible triggers. Laboratory testing should be considered if the history or physical examination raises suspicion for either condition. Diabetes has also been associated with the disseminated form and the literature suggests a connection with autoimmune diseases of the liver and thyroid.1
Watchful waiting is usually the best treatment for localized disease, which can spontaneously regress within a year and is usually asymptomatic. Intralesional steroid injections into the raised annulus are more effective than topical steroids, as the effects of the topical steroids are sometimes augmented by occlusion.
Multiple treatments have been proposed for DGA, including UVA treatments, systemic retinoids, doxycycline, and hydroxychloroquine.1 Unfortunately, the disseminated form can persist for many years—even with treatment.
Due to the extent of the lesions, the patient in this case was not interested in intralesional steroid injections, and she had already tried topical steroids. She was prescribed topical tacrolimus to reduce the highly visible nature of her lesions.
Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.
This patient was given a diagnosis of disseminated granuloma annulare (DGA). While granuloma annulare usually manifests as a single lesion with a raised erythematous border (often with central pallor or hypopigmentation) it can also manifest as multiple large annular lesions on the extremities and occasionally the trunk, as was seen with this case of DGA.
Although the etiology of DGA is unknown, infections including HIV and hepatitis have been reported as possible triggers. Laboratory testing should be considered if the history or physical examination raises suspicion for either condition. Diabetes has also been associated with the disseminated form and the literature suggests a connection with autoimmune diseases of the liver and thyroid.1
Watchful waiting is usually the best treatment for localized disease, which can spontaneously regress within a year and is usually asymptomatic. Intralesional steroid injections into the raised annulus are more effective than topical steroids, as the effects of the topical steroids are sometimes augmented by occlusion.
Multiple treatments have been proposed for DGA, including UVA treatments, systemic retinoids, doxycycline, and hydroxychloroquine.1 Unfortunately, the disseminated form can persist for many years—even with treatment.
Due to the extent of the lesions, the patient in this case was not interested in intralesional steroid injections, and she had already tried topical steroids. She was prescribed topical tacrolimus to reduce the highly visible nature of her lesions.
Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.
Beretta-Piccoli BT, Mainetti C, Peeters MA, et al. Cutaneous granulomatosis: a comprehensive review. Clin Rev Allergy Immunol. 2018;54:131-146. doi: 10.1007/s12016-017-8666-8
Beretta-Piccoli BT, Mainetti C, Peeters MA, et al. Cutaneous granulomatosis: a comprehensive review. Clin Rev Allergy Immunol. 2018;54:131-146. doi: 10.1007/s12016-017-8666-8
What’s under my toenail?
After the teledermatology consultation, an x-ray was recommended. The x-ray showed an elongated irregular radiopaque mass projecting from the anterior medial aspect of the midshaft of the distal phalanx of the great toe (Picture 3). With these findings, subungual exostosis was suspected, and she was referred to orthopedic surgery for excision of the lesion. Histopathology showed a stack of trabecular bone with a fibrocartilaginous cap, confirming the diagnosis of subungual exostosis.
Subungual exostosis is a benign osteocartilaginous tumor, first described by Dupuytren in 1874. These lesions are rare and are seen mainly in children and young adults. Females appear to be affected more often than males.1 In a systematic review by DaCambra and colleagues, 55% of the cases occur in patients aged younger than 18 years, and the hallux was the most commonly affected digit, though any finger or toe can be affected.2 There are reported case of congenital multiple exostosis delineated to translocation t(X;6)(q22;q13-14).3
The exact cause of these lesions is unknown, but there are multiple theories, which include a reactive process secondary to trauma, infection, or genetic causes. Pathologic examination of the lesions shows an osseous center covered by a fibrocartilaginous cap. There is proliferation of spindle cells that generate cartilage, which later forms trabecular bone.4
On physical examination, subungual exostosis appear like a firm, fixed nodule with a hyperkeratotic smooth surface at the distal end of the nail bed, that slowly grows and can distort and lift up the nail. Dermoscopy features of these lesions include vascular ectasia, hyperkeratosis, onycholysis, and ulceration.
The differential diagnosis of subungual growths includes osteochondromas, which can present in a similar way but are rarer. Pathologic examination is usually required to differentiate between both lesions.5 In exostoses, bone is formed directly from fibrous tissue, whereas in osteochondromas they derive from enchondral ossification.6 The cartilaginous cap of this lesion is what helps to differentiate it in histopathology. In subungual exostosis, the cap is composed of fibrocartilage, while in osteochondromas it is made of hyaline cartilage similar to what is seen in normal growing epiphysis.5 Subungual exostosis can be confused with pyogenic granulomas and verruca, and often are treated as such, which delays appropriate surgical management.
Firm, slow-growing tumors in the fingers or toes of children should raise suspicion for underlying bony lesions like subungual exostosis and osteochondromas. X-rays of the lesion should be performed in order to clarify the diagnosis. Referral to orthopedic surgery is needed for definitive surgical management.
Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego.
References
1. Zhang W et al. JAAD Case Rep. 2020 Jun 1;6(8):725-6.
2. DaCambra MP et al. Clin Orthop Relat Res. 2014 Apr;472(4):1251-9.
3. Torlazzi C et al. Int J Cancer. 2006;118:1972-6.
4. Calonje E et al. McKee’s pathology of the skin: With clinical correlations. (4th ed.) Philadelphia: Elsevier/Saunders, 2012.
5. Lee SK et al. Foot Ankle Int. 2007 May;28(5):595-601.
6. Mavrogenis A et al. Orthopedics. 2008 Oct;31(10).
After the teledermatology consultation, an x-ray was recommended. The x-ray showed an elongated irregular radiopaque mass projecting from the anterior medial aspect of the midshaft of the distal phalanx of the great toe (Picture 3). With these findings, subungual exostosis was suspected, and she was referred to orthopedic surgery for excision of the lesion. Histopathology showed a stack of trabecular bone with a fibrocartilaginous cap, confirming the diagnosis of subungual exostosis.
Subungual exostosis is a benign osteocartilaginous tumor, first described by Dupuytren in 1874. These lesions are rare and are seen mainly in children and young adults. Females appear to be affected more often than males.1 In a systematic review by DaCambra and colleagues, 55% of the cases occur in patients aged younger than 18 years, and the hallux was the most commonly affected digit, though any finger or toe can be affected.2 There are reported case of congenital multiple exostosis delineated to translocation t(X;6)(q22;q13-14).3
The exact cause of these lesions is unknown, but there are multiple theories, which include a reactive process secondary to trauma, infection, or genetic causes. Pathologic examination of the lesions shows an osseous center covered by a fibrocartilaginous cap. There is proliferation of spindle cells that generate cartilage, which later forms trabecular bone.4
On physical examination, subungual exostosis appear like a firm, fixed nodule with a hyperkeratotic smooth surface at the distal end of the nail bed, that slowly grows and can distort and lift up the nail. Dermoscopy features of these lesions include vascular ectasia, hyperkeratosis, onycholysis, and ulceration.
The differential diagnosis of subungual growths includes osteochondromas, which can present in a similar way but are rarer. Pathologic examination is usually required to differentiate between both lesions.5 In exostoses, bone is formed directly from fibrous tissue, whereas in osteochondromas they derive from enchondral ossification.6 The cartilaginous cap of this lesion is what helps to differentiate it in histopathology. In subungual exostosis, the cap is composed of fibrocartilage, while in osteochondromas it is made of hyaline cartilage similar to what is seen in normal growing epiphysis.5 Subungual exostosis can be confused with pyogenic granulomas and verruca, and often are treated as such, which delays appropriate surgical management.
Firm, slow-growing tumors in the fingers or toes of children should raise suspicion for underlying bony lesions like subungual exostosis and osteochondromas. X-rays of the lesion should be performed in order to clarify the diagnosis. Referral to orthopedic surgery is needed for definitive surgical management.
Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego.
References
1. Zhang W et al. JAAD Case Rep. 2020 Jun 1;6(8):725-6.
2. DaCambra MP et al. Clin Orthop Relat Res. 2014 Apr;472(4):1251-9.
3. Torlazzi C et al. Int J Cancer. 2006;118:1972-6.
4. Calonje E et al. McKee’s pathology of the skin: With clinical correlations. (4th ed.) Philadelphia: Elsevier/Saunders, 2012.
5. Lee SK et al. Foot Ankle Int. 2007 May;28(5):595-601.
6. Mavrogenis A et al. Orthopedics. 2008 Oct;31(10).
After the teledermatology consultation, an x-ray was recommended. The x-ray showed an elongated irregular radiopaque mass projecting from the anterior medial aspect of the midshaft of the distal phalanx of the great toe (Picture 3). With these findings, subungual exostosis was suspected, and she was referred to orthopedic surgery for excision of the lesion. Histopathology showed a stack of trabecular bone with a fibrocartilaginous cap, confirming the diagnosis of subungual exostosis.
Subungual exostosis is a benign osteocartilaginous tumor, first described by Dupuytren in 1874. These lesions are rare and are seen mainly in children and young adults. Females appear to be affected more often than males.1 In a systematic review by DaCambra and colleagues, 55% of the cases occur in patients aged younger than 18 years, and the hallux was the most commonly affected digit, though any finger or toe can be affected.2 There are reported case of congenital multiple exostosis delineated to translocation t(X;6)(q22;q13-14).3
The exact cause of these lesions is unknown, but there are multiple theories, which include a reactive process secondary to trauma, infection, or genetic causes. Pathologic examination of the lesions shows an osseous center covered by a fibrocartilaginous cap. There is proliferation of spindle cells that generate cartilage, which later forms trabecular bone.4
On physical examination, subungual exostosis appear like a firm, fixed nodule with a hyperkeratotic smooth surface at the distal end of the nail bed, that slowly grows and can distort and lift up the nail. Dermoscopy features of these lesions include vascular ectasia, hyperkeratosis, onycholysis, and ulceration.
The differential diagnosis of subungual growths includes osteochondromas, which can present in a similar way but are rarer. Pathologic examination is usually required to differentiate between both lesions.5 In exostoses, bone is formed directly from fibrous tissue, whereas in osteochondromas they derive from enchondral ossification.6 The cartilaginous cap of this lesion is what helps to differentiate it in histopathology. In subungual exostosis, the cap is composed of fibrocartilage, while in osteochondromas it is made of hyaline cartilage similar to what is seen in normal growing epiphysis.5 Subungual exostosis can be confused with pyogenic granulomas and verruca, and often are treated as such, which delays appropriate surgical management.
Firm, slow-growing tumors in the fingers or toes of children should raise suspicion for underlying bony lesions like subungual exostosis and osteochondromas. X-rays of the lesion should be performed in order to clarify the diagnosis. Referral to orthopedic surgery is needed for definitive surgical management.
Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego.
References
1. Zhang W et al. JAAD Case Rep. 2020 Jun 1;6(8):725-6.
2. DaCambra MP et al. Clin Orthop Relat Res. 2014 Apr;472(4):1251-9.
3. Torlazzi C et al. Int J Cancer. 2006;118:1972-6.
4. Calonje E et al. McKee’s pathology of the skin: With clinical correlations. (4th ed.) Philadelphia: Elsevier/Saunders, 2012.
5. Lee SK et al. Foot Ankle Int. 2007 May;28(5):595-601.
6. Mavrogenis A et al. Orthopedics. 2008 Oct;31(10).
A 13-year-old female was seen by her pediatrician for a lesion that had been on her right toe for about 6 months. She is unaware of any trauma to the area. The lesion has been growing slowly and recently it started lifting up the nail, became tender, and was bleeding, which is the reason why she sought care.
At the pediatrician's office, he noted a pink crusted papule under the nail. The nail was lifting up and was tender to the touch. She is a healthy girl who is not taking any medications and has no allergies. There is no family history of similar lesions.
The pediatrician took a picture of the lesion and he send it to our pediatric teledermatology service for consultation.
A 35-year-old with erythematous, dusky patches on both lower extremities
Zinc deficiency may be inherited or acquired. Acrodermatitis enteropathica is an autosomal recessive genetic disorder caused by a mutation in the gene that encodes a zinc transporter. It presents in infancy with the classic triad of diarrhea, dermatitis, and alopecia. Acquired zinc deficiency is due to causes such as alcoholism, malabsorption disorders like cystic fibrosis, inflammatory disease, gastrointestinal surgery, metabolic stress following general surgery, eating disorders, infections, malignancy, or occasionally in pregnancy. Classically, the face, groin, and extremities are affected (often acral), with erythematous, scaly patches. Pustules and bullae may be present. Angular cheilitis is often seen.
Necrolytic migratory erythema, or glucagonoma syndrome, is a very rare syndrome that presents as annular, erythematous patches with blisters that erode on the lower extremities and groin. The condition results from a cancerous tumor in the alpha cells of the pancreas called a glucagonoma, which secretes the hormone glucagon. It is often associated with diabetes and hyperglycemia.
Necrolytic acral erythema resembles acrodermatitis enteropathica and necrolytic migratory erythema clinically, however, it is associated with hepatitis C infection. Lesions are plaques with well defined borders distributed acrally. Treatment of the hepatitis C often improves the dermatitis.
Our patient’s blood work was consistent with nutritional deficiency and revealed low levels of zinc, vitamin A, ceruloplasmin, albumin and prealbumin, total protein, calcium, selenium, vitamin E, vitamin K, and vitamin C. Her hemoglobin A1C was under 4. Her hepatitis serologies were negative. The patient received total parenteral nutrition with subsequent complete resolution of her rash. Follow up for gastric bypass patients should be performed long term as they are at risk for nutritional deficiencies.
Dr. Bilu Martin, and Andrew Harris, DO, Mount Sinai Medical Center, Aventura, Fla., provided the case and photos.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.
References
Dermatol Online J. 2016 Nov 15; 22(11):13030.
Andrews’ Disease of the Skin: Clinical Dermatology. Philadelphia: Saunders Elsevier, 2006.
Bolognia et al. Dermatology. St. Louis: Mosby/Elsevier, 2008.
Zinc deficiency may be inherited or acquired. Acrodermatitis enteropathica is an autosomal recessive genetic disorder caused by a mutation in the gene that encodes a zinc transporter. It presents in infancy with the classic triad of diarrhea, dermatitis, and alopecia. Acquired zinc deficiency is due to causes such as alcoholism, malabsorption disorders like cystic fibrosis, inflammatory disease, gastrointestinal surgery, metabolic stress following general surgery, eating disorders, infections, malignancy, or occasionally in pregnancy. Classically, the face, groin, and extremities are affected (often acral), with erythematous, scaly patches. Pustules and bullae may be present. Angular cheilitis is often seen.
Necrolytic migratory erythema, or glucagonoma syndrome, is a very rare syndrome that presents as annular, erythematous patches with blisters that erode on the lower extremities and groin. The condition results from a cancerous tumor in the alpha cells of the pancreas called a glucagonoma, which secretes the hormone glucagon. It is often associated with diabetes and hyperglycemia.
Necrolytic acral erythema resembles acrodermatitis enteropathica and necrolytic migratory erythema clinically, however, it is associated with hepatitis C infection. Lesions are plaques with well defined borders distributed acrally. Treatment of the hepatitis C often improves the dermatitis.
Our patient’s blood work was consistent with nutritional deficiency and revealed low levels of zinc, vitamin A, ceruloplasmin, albumin and prealbumin, total protein, calcium, selenium, vitamin E, vitamin K, and vitamin C. Her hemoglobin A1C was under 4. Her hepatitis serologies were negative. The patient received total parenteral nutrition with subsequent complete resolution of her rash. Follow up for gastric bypass patients should be performed long term as they are at risk for nutritional deficiencies.
Dr. Bilu Martin, and Andrew Harris, DO, Mount Sinai Medical Center, Aventura, Fla., provided the case and photos.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.
References
Dermatol Online J. 2016 Nov 15; 22(11):13030.
Andrews’ Disease of the Skin: Clinical Dermatology. Philadelphia: Saunders Elsevier, 2006.
Bolognia et al. Dermatology. St. Louis: Mosby/Elsevier, 2008.
Zinc deficiency may be inherited or acquired. Acrodermatitis enteropathica is an autosomal recessive genetic disorder caused by a mutation in the gene that encodes a zinc transporter. It presents in infancy with the classic triad of diarrhea, dermatitis, and alopecia. Acquired zinc deficiency is due to causes such as alcoholism, malabsorption disorders like cystic fibrosis, inflammatory disease, gastrointestinal surgery, metabolic stress following general surgery, eating disorders, infections, malignancy, or occasionally in pregnancy. Classically, the face, groin, and extremities are affected (often acral), with erythematous, scaly patches. Pustules and bullae may be present. Angular cheilitis is often seen.
Necrolytic migratory erythema, or glucagonoma syndrome, is a very rare syndrome that presents as annular, erythematous patches with blisters that erode on the lower extremities and groin. The condition results from a cancerous tumor in the alpha cells of the pancreas called a glucagonoma, which secretes the hormone glucagon. It is often associated with diabetes and hyperglycemia.
Necrolytic acral erythema resembles acrodermatitis enteropathica and necrolytic migratory erythema clinically, however, it is associated with hepatitis C infection. Lesions are plaques with well defined borders distributed acrally. Treatment of the hepatitis C often improves the dermatitis.
Our patient’s blood work was consistent with nutritional deficiency and revealed low levels of zinc, vitamin A, ceruloplasmin, albumin and prealbumin, total protein, calcium, selenium, vitamin E, vitamin K, and vitamin C. Her hemoglobin A1C was under 4. Her hepatitis serologies were negative. The patient received total parenteral nutrition with subsequent complete resolution of her rash. Follow up for gastric bypass patients should be performed long term as they are at risk for nutritional deficiencies.
Dr. Bilu Martin, and Andrew Harris, DO, Mount Sinai Medical Center, Aventura, Fla., provided the case and photos.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.
References
Dermatol Online J. 2016 Nov 15; 22(11):13030.
Andrews’ Disease of the Skin: Clinical Dermatology. Philadelphia: Saunders Elsevier, 2006.
Bolognia et al. Dermatology. St. Louis: Mosby/Elsevier, 2008.
Western diet promoted skin, joint inflammation in preclinical study
A short-term Western diet facilitated the development of interleukin (IL)-23-mediated psoriasis-like skin and joint inflammation and caused shifts in the intestinal microbiota in a murine model – , say the investigators and other experts who reviewed the findings.
The mice did not become obese during the short duration of the multilayered study, which suggests that a Western diet (high sugar, moderate fat) can be impactful independent of obesity, Samuel T. Hwang, MD, PhD, professor and chair of dermatology at the University of California, Davis, and senior author of the study, said in an interview. The study was published in the Journal of Investigative Dermatology.
In an accompanying commentary, Renuka R. Nayak, MD, PhD, of the department of rheumatology at the University of California, San Francisco, wrote that the findings “add to the mounting evidence suggesting that diet has a prominent role in the treatment of psoriasis and [psoriatic arthritis] and raise the possibility that the microbiome may contribute to disease severity”.
Mice were fed a Western diet (WD) or conventional chow diet for 6 weeks and then injected with IL-23 minicircle (MC) DNA to induce systemic IL-23 overexpression – or a control minicircle DNA injection – and continued on these diets for another 4 weeks.
The mice in the WD/IL-23 MC DNA group developed erythema and scaling and increased epidermal thickness in the ears; such changes were “remarkably milder” or nonexistent in the other groups. Skin and joint immune cell populations, such as gamma delta T cells, neutrophils, and T helper type 17 cytokines were elevated in WD-fed mice, as were other markers of IL-23-mediated joint inflammation.
Recent research has suggested that the gut microbiota is dysbiotic in patients with psoriasis, and this new study found that WD-fed mice had less microbial diversity than that of mice fed a conventional diet. After IL-23 MC delivery, WD-fed reduced microbial diversity and pronounced dysbiosis.
“When we combined the Western diet and IL-23, we saw some very different microbes in abundance. The whole landscape changed,” Dr. Hwang said in the interview.
The data “suggest that WD and overexpression of IL-23 may contribute to gut microbiota dysbiosis in a synergistic and complex manner,” he and his coinvestigators wrote.
Treatment with broad-spectrum antibiotics suppressed IL-23-mediated skin and joint inflammation in the WD-fed mice – and moderately affected skin inflammation in conventionally-fed mice as well – which affirmed the role of dysbiosis.
And “notably,” in another layer of the study, mice that switched diets from a WD to a conventional diet had reduced skin and joint inflammation and increased diversity of gut microbiota. (Mice that were fed a WD for 6 weeks and given the IL-23 MC DNA were randomized to continue this diet for another 4 weeks or switch to a conventional diet.)
Commenting on the new research, Wilson Liao, MD, professor and vice chair of research in the department of dermatology at the University of California, San Francisco, said it “provides evidence” that diet can affect not only psoriasis, but psoriatic arthritis (PsA) as well, “through altering the ratio of good to bad bacteria in the gut.”
Going forward, better understanding “which specific gut bacteria and bacterial products lead to increased psoriatic inflammation, and the immunologic mechanism by which this occurs” will be important and could lead to novel treatments for psoriasis and PsA, said Dr. Liao, director of the UCSF Psoriasis and Skin Treatment Center.
Next on his research agenda, Dr. Hwang said, is the question of “how microbiota in the gut are actually able to influence inflammation at very distant sites in the joints and the skin.
“We want to understand the metabolic mechanisms,” he said, noting that “we invariably talk about cytokines, but there are other substances, like certain bile acids that are metabolized through the gut microbiome,” which may play a role.
The findings also offer a basis for treatment experiments in humans – of diet, probiotic therapy, or selective antibiotic modulation, for instance, Dr. Hwang said.
And in the meantime, the findings should encourage patients who are interested in making dietary changes, such as reducing sugar intake. “There’s wide interest – patients will ask, is there something I can change to make this better?” Dr. Hwang said. “Before, we could say it might be logical, but now we have some evidence. The message now is [high-sugar, moderate-fat] diets, apart from their ability to stimulate obesity, probably have some effects.”
Dietary change may not replace the need for other psoriasis treatments, he said, “but I think there’s good reason to believe that if you do change your diet, your treatment will be better than it would be without that dietary change,” he said.
In their discussion, Dr. Hwang and coauthors note that WD with IL-23 overexpression also decreased the mRNA expression of barrier-forming tight junction proteins, thus increasing intestinal permeability. This finding may be relevant, they wrote, because “leaky gut has been proposed as a pathogenic link between unhealthy diet, gut dysbiosis, and enhanced immune response,” and has been observed in a number of autoimmune diseases, including psoriasis.
Dr. Hwang, lead author Zhenrui Shi, MD, PhD, and coauthors reported no conflicts of interest. Their study was supported by the National Psoriasis Foundation, as well as the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Cancer Institute.
A short-term Western diet facilitated the development of interleukin (IL)-23-mediated psoriasis-like skin and joint inflammation and caused shifts in the intestinal microbiota in a murine model – , say the investigators and other experts who reviewed the findings.
The mice did not become obese during the short duration of the multilayered study, which suggests that a Western diet (high sugar, moderate fat) can be impactful independent of obesity, Samuel T. Hwang, MD, PhD, professor and chair of dermatology at the University of California, Davis, and senior author of the study, said in an interview. The study was published in the Journal of Investigative Dermatology.
In an accompanying commentary, Renuka R. Nayak, MD, PhD, of the department of rheumatology at the University of California, San Francisco, wrote that the findings “add to the mounting evidence suggesting that diet has a prominent role in the treatment of psoriasis and [psoriatic arthritis] and raise the possibility that the microbiome may contribute to disease severity”.
Mice were fed a Western diet (WD) or conventional chow diet for 6 weeks and then injected with IL-23 minicircle (MC) DNA to induce systemic IL-23 overexpression – or a control minicircle DNA injection – and continued on these diets for another 4 weeks.
The mice in the WD/IL-23 MC DNA group developed erythema and scaling and increased epidermal thickness in the ears; such changes were “remarkably milder” or nonexistent in the other groups. Skin and joint immune cell populations, such as gamma delta T cells, neutrophils, and T helper type 17 cytokines were elevated in WD-fed mice, as were other markers of IL-23-mediated joint inflammation.
Recent research has suggested that the gut microbiota is dysbiotic in patients with psoriasis, and this new study found that WD-fed mice had less microbial diversity than that of mice fed a conventional diet. After IL-23 MC delivery, WD-fed reduced microbial diversity and pronounced dysbiosis.
“When we combined the Western diet and IL-23, we saw some very different microbes in abundance. The whole landscape changed,” Dr. Hwang said in the interview.
The data “suggest that WD and overexpression of IL-23 may contribute to gut microbiota dysbiosis in a synergistic and complex manner,” he and his coinvestigators wrote.
Treatment with broad-spectrum antibiotics suppressed IL-23-mediated skin and joint inflammation in the WD-fed mice – and moderately affected skin inflammation in conventionally-fed mice as well – which affirmed the role of dysbiosis.
And “notably,” in another layer of the study, mice that switched diets from a WD to a conventional diet had reduced skin and joint inflammation and increased diversity of gut microbiota. (Mice that were fed a WD for 6 weeks and given the IL-23 MC DNA were randomized to continue this diet for another 4 weeks or switch to a conventional diet.)
Commenting on the new research, Wilson Liao, MD, professor and vice chair of research in the department of dermatology at the University of California, San Francisco, said it “provides evidence” that diet can affect not only psoriasis, but psoriatic arthritis (PsA) as well, “through altering the ratio of good to bad bacteria in the gut.”
Going forward, better understanding “which specific gut bacteria and bacterial products lead to increased psoriatic inflammation, and the immunologic mechanism by which this occurs” will be important and could lead to novel treatments for psoriasis and PsA, said Dr. Liao, director of the UCSF Psoriasis and Skin Treatment Center.
Next on his research agenda, Dr. Hwang said, is the question of “how microbiota in the gut are actually able to influence inflammation at very distant sites in the joints and the skin.
“We want to understand the metabolic mechanisms,” he said, noting that “we invariably talk about cytokines, but there are other substances, like certain bile acids that are metabolized through the gut microbiome,” which may play a role.
The findings also offer a basis for treatment experiments in humans – of diet, probiotic therapy, or selective antibiotic modulation, for instance, Dr. Hwang said.
And in the meantime, the findings should encourage patients who are interested in making dietary changes, such as reducing sugar intake. “There’s wide interest – patients will ask, is there something I can change to make this better?” Dr. Hwang said. “Before, we could say it might be logical, but now we have some evidence. The message now is [high-sugar, moderate-fat] diets, apart from their ability to stimulate obesity, probably have some effects.”
Dietary change may not replace the need for other psoriasis treatments, he said, “but I think there’s good reason to believe that if you do change your diet, your treatment will be better than it would be without that dietary change,” he said.
In their discussion, Dr. Hwang and coauthors note that WD with IL-23 overexpression also decreased the mRNA expression of barrier-forming tight junction proteins, thus increasing intestinal permeability. This finding may be relevant, they wrote, because “leaky gut has been proposed as a pathogenic link between unhealthy diet, gut dysbiosis, and enhanced immune response,” and has been observed in a number of autoimmune diseases, including psoriasis.
Dr. Hwang, lead author Zhenrui Shi, MD, PhD, and coauthors reported no conflicts of interest. Their study was supported by the National Psoriasis Foundation, as well as the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Cancer Institute.
A short-term Western diet facilitated the development of interleukin (IL)-23-mediated psoriasis-like skin and joint inflammation and caused shifts in the intestinal microbiota in a murine model – , say the investigators and other experts who reviewed the findings.
The mice did not become obese during the short duration of the multilayered study, which suggests that a Western diet (high sugar, moderate fat) can be impactful independent of obesity, Samuel T. Hwang, MD, PhD, professor and chair of dermatology at the University of California, Davis, and senior author of the study, said in an interview. The study was published in the Journal of Investigative Dermatology.
In an accompanying commentary, Renuka R. Nayak, MD, PhD, of the department of rheumatology at the University of California, San Francisco, wrote that the findings “add to the mounting evidence suggesting that diet has a prominent role in the treatment of psoriasis and [psoriatic arthritis] and raise the possibility that the microbiome may contribute to disease severity”.
Mice were fed a Western diet (WD) or conventional chow diet for 6 weeks and then injected with IL-23 minicircle (MC) DNA to induce systemic IL-23 overexpression – or a control minicircle DNA injection – and continued on these diets for another 4 weeks.
The mice in the WD/IL-23 MC DNA group developed erythema and scaling and increased epidermal thickness in the ears; such changes were “remarkably milder” or nonexistent in the other groups. Skin and joint immune cell populations, such as gamma delta T cells, neutrophils, and T helper type 17 cytokines were elevated in WD-fed mice, as were other markers of IL-23-mediated joint inflammation.
Recent research has suggested that the gut microbiota is dysbiotic in patients with psoriasis, and this new study found that WD-fed mice had less microbial diversity than that of mice fed a conventional diet. After IL-23 MC delivery, WD-fed reduced microbial diversity and pronounced dysbiosis.
“When we combined the Western diet and IL-23, we saw some very different microbes in abundance. The whole landscape changed,” Dr. Hwang said in the interview.
The data “suggest that WD and overexpression of IL-23 may contribute to gut microbiota dysbiosis in a synergistic and complex manner,” he and his coinvestigators wrote.
Treatment with broad-spectrum antibiotics suppressed IL-23-mediated skin and joint inflammation in the WD-fed mice – and moderately affected skin inflammation in conventionally-fed mice as well – which affirmed the role of dysbiosis.
And “notably,” in another layer of the study, mice that switched diets from a WD to a conventional diet had reduced skin and joint inflammation and increased diversity of gut microbiota. (Mice that were fed a WD for 6 weeks and given the IL-23 MC DNA were randomized to continue this diet for another 4 weeks or switch to a conventional diet.)
Commenting on the new research, Wilson Liao, MD, professor and vice chair of research in the department of dermatology at the University of California, San Francisco, said it “provides evidence” that diet can affect not only psoriasis, but psoriatic arthritis (PsA) as well, “through altering the ratio of good to bad bacteria in the gut.”
Going forward, better understanding “which specific gut bacteria and bacterial products lead to increased psoriatic inflammation, and the immunologic mechanism by which this occurs” will be important and could lead to novel treatments for psoriasis and PsA, said Dr. Liao, director of the UCSF Psoriasis and Skin Treatment Center.
Next on his research agenda, Dr. Hwang said, is the question of “how microbiota in the gut are actually able to influence inflammation at very distant sites in the joints and the skin.
“We want to understand the metabolic mechanisms,” he said, noting that “we invariably talk about cytokines, but there are other substances, like certain bile acids that are metabolized through the gut microbiome,” which may play a role.
The findings also offer a basis for treatment experiments in humans – of diet, probiotic therapy, or selective antibiotic modulation, for instance, Dr. Hwang said.
And in the meantime, the findings should encourage patients who are interested in making dietary changes, such as reducing sugar intake. “There’s wide interest – patients will ask, is there something I can change to make this better?” Dr. Hwang said. “Before, we could say it might be logical, but now we have some evidence. The message now is [high-sugar, moderate-fat] diets, apart from their ability to stimulate obesity, probably have some effects.”
Dietary change may not replace the need for other psoriasis treatments, he said, “but I think there’s good reason to believe that if you do change your diet, your treatment will be better than it would be without that dietary change,” he said.
In their discussion, Dr. Hwang and coauthors note that WD with IL-23 overexpression also decreased the mRNA expression of barrier-forming tight junction proteins, thus increasing intestinal permeability. This finding may be relevant, they wrote, because “leaky gut has been proposed as a pathogenic link between unhealthy diet, gut dysbiosis, and enhanced immune response,” and has been observed in a number of autoimmune diseases, including psoriasis.
Dr. Hwang, lead author Zhenrui Shi, MD, PhD, and coauthors reported no conflicts of interest. Their study was supported by the National Psoriasis Foundation, as well as the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Cancer Institute.
FROM THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
Age, distance from dermatology clinic <p>predict number of melanomas diagnosed
Among patients from a single dermatology practice who were diagnosed with two or more melanomas over an 8-year period, 45% lived more than 20 miles away from the practice, and almost 60% were 70 years of age and older, results from single-center study showed.
“Dermatologists have known that many people are underdiagnosed for melanoma, but now our research supports that the problem is especially concentrated among older patients living in remote areas,” corresponding author Rose Parisi, MBA, said in an interview. “With this information, dermatologists should consider identifying and reaching out to their patients in this at-risk subpopulation, increasing the frequency of full-body skin exams, and collaborating with primary care physicians to educate them about melanoma’s dangers.”
In a study published online Aug. 3 in the Journal of the American Academy of Dermatology, Ms. Parisi of Albany Medical College, New York, and colleagues drew from the electronic medical records of a single-specialty private dermatology practice that serves urban, suburban, and rural patient populations to identify 346 melanoma pathology reports from patients cared for between 2012 and 2020. They limited their investigation to those diagnosed with biopsy-confirmed melanoma and analyzed the number of melanomas, Breslow depth, follow-up full-body skin exams, family history of melanoma, gender, insurance, and age (categorized as younger than 70 years and 70 years or older). To determine patient travel distance, they calculated the miles between the ZIP codes of the patient’s residence and the dermatology practice.
Regression analysis revealed that the . Specifically, among patients diagnosed with two or more melanomas, 45.0% lived more than 20 miles away and 21.3% lived less than 15 miles away; 59.6% were age 70 and older, while 40.4% were younger than age 70 (P less than .01).
No statistically significant association was observed between travel distance and Breslow depth or follow-up full-body skin exams within 1 year following diagnosis.
In other findings, among patients who lived more than 20 miles from the practice, those aged 70 and older were diagnosed with 0.56 more melanomas than patients between the ages of 58 and 70 (P = .00003), and 0.31 more melanomas than patients who lived 15-20 miles away (P = .014). No statistically significant differences in the number of melanomas diagnosed were observed between patients in either age group who lived fewer than 15 miles from the office.
“We were surprised that the combination of age and patient distance to diagnosing dermatology provider was such a powerful predictor of the number of diagnosed melanomas,” Ms. Parisi said. “It’s probably due to less mobility among older patients living in more remote areas, and it puts them at higher risk of multiple melanomas. This was something we haven’t seen in the dermatology literature.”
She and her coauthors acknowledged that the limited sampling of patients from a single practice “may not generalize across all urban and rural settings, and results must be considered preliminary,” they wrote. However, “our findings reveal an important vulnerability among older patients in nonurban areas, and efforts to improve access to melanoma diagnosis should be concentrated on this geodemographic segment.”
Nikolai Klebanov, MD, of the department of dermatology at Massachusetts General Hospital, Boston, who was asked to comment on the study, described what was addressed in the study as a “timely and an important topic.”
In an interview, he said, “there is less access to dermatologists and other medical specialists outside of large metropolitan and suburban areas,” and there are other health disparities affecting people living in rural or more underserved areas, which, he added, “also became exacerbated by the COVID-19 pandemic.”
For future studies on this topic, Dr. Klebanov said that he would be interested to see diagnoses measured per person-year rather than the total number of melanomas diagnosed. “More elderly patients may also be those who have ‘stuck with the practice’ for longer, and had a longer follow-up that gives more time to catch more melanomas,” he said.
“Adjusting for median income using ZIP codes could also help adjust for socioeconomic status, which would help with external validity of the study. Income relationships to geography are not the same in all cities; some have wealthy suburbs within 20 miles, while some have more underserved and rural areas at that distance.”
Neither the researchers nor Dr. Klebanov reported having financial disclosures.
Among patients from a single dermatology practice who were diagnosed with two or more melanomas over an 8-year period, 45% lived more than 20 miles away from the practice, and almost 60% were 70 years of age and older, results from single-center study showed.
“Dermatologists have known that many people are underdiagnosed for melanoma, but now our research supports that the problem is especially concentrated among older patients living in remote areas,” corresponding author Rose Parisi, MBA, said in an interview. “With this information, dermatologists should consider identifying and reaching out to their patients in this at-risk subpopulation, increasing the frequency of full-body skin exams, and collaborating with primary care physicians to educate them about melanoma’s dangers.”
In a study published online Aug. 3 in the Journal of the American Academy of Dermatology, Ms. Parisi of Albany Medical College, New York, and colleagues drew from the electronic medical records of a single-specialty private dermatology practice that serves urban, suburban, and rural patient populations to identify 346 melanoma pathology reports from patients cared for between 2012 and 2020. They limited their investigation to those diagnosed with biopsy-confirmed melanoma and analyzed the number of melanomas, Breslow depth, follow-up full-body skin exams, family history of melanoma, gender, insurance, and age (categorized as younger than 70 years and 70 years or older). To determine patient travel distance, they calculated the miles between the ZIP codes of the patient’s residence and the dermatology practice.
Regression analysis revealed that the . Specifically, among patients diagnosed with two or more melanomas, 45.0% lived more than 20 miles away and 21.3% lived less than 15 miles away; 59.6% were age 70 and older, while 40.4% were younger than age 70 (P less than .01).
No statistically significant association was observed between travel distance and Breslow depth or follow-up full-body skin exams within 1 year following diagnosis.
In other findings, among patients who lived more than 20 miles from the practice, those aged 70 and older were diagnosed with 0.56 more melanomas than patients between the ages of 58 and 70 (P = .00003), and 0.31 more melanomas than patients who lived 15-20 miles away (P = .014). No statistically significant differences in the number of melanomas diagnosed were observed between patients in either age group who lived fewer than 15 miles from the office.
“We were surprised that the combination of age and patient distance to diagnosing dermatology provider was such a powerful predictor of the number of diagnosed melanomas,” Ms. Parisi said. “It’s probably due to less mobility among older patients living in more remote areas, and it puts them at higher risk of multiple melanomas. This was something we haven’t seen in the dermatology literature.”
She and her coauthors acknowledged that the limited sampling of patients from a single practice “may not generalize across all urban and rural settings, and results must be considered preliminary,” they wrote. However, “our findings reveal an important vulnerability among older patients in nonurban areas, and efforts to improve access to melanoma diagnosis should be concentrated on this geodemographic segment.”
Nikolai Klebanov, MD, of the department of dermatology at Massachusetts General Hospital, Boston, who was asked to comment on the study, described what was addressed in the study as a “timely and an important topic.”
In an interview, he said, “there is less access to dermatologists and other medical specialists outside of large metropolitan and suburban areas,” and there are other health disparities affecting people living in rural or more underserved areas, which, he added, “also became exacerbated by the COVID-19 pandemic.”
For future studies on this topic, Dr. Klebanov said that he would be interested to see diagnoses measured per person-year rather than the total number of melanomas diagnosed. “More elderly patients may also be those who have ‘stuck with the practice’ for longer, and had a longer follow-up that gives more time to catch more melanomas,” he said.
“Adjusting for median income using ZIP codes could also help adjust for socioeconomic status, which would help with external validity of the study. Income relationships to geography are not the same in all cities; some have wealthy suburbs within 20 miles, while some have more underserved and rural areas at that distance.”
Neither the researchers nor Dr. Klebanov reported having financial disclosures.
Among patients from a single dermatology practice who were diagnosed with two or more melanomas over an 8-year period, 45% lived more than 20 miles away from the practice, and almost 60% were 70 years of age and older, results from single-center study showed.
“Dermatologists have known that many people are underdiagnosed for melanoma, but now our research supports that the problem is especially concentrated among older patients living in remote areas,” corresponding author Rose Parisi, MBA, said in an interview. “With this information, dermatologists should consider identifying and reaching out to their patients in this at-risk subpopulation, increasing the frequency of full-body skin exams, and collaborating with primary care physicians to educate them about melanoma’s dangers.”
In a study published online Aug. 3 in the Journal of the American Academy of Dermatology, Ms. Parisi of Albany Medical College, New York, and colleagues drew from the electronic medical records of a single-specialty private dermatology practice that serves urban, suburban, and rural patient populations to identify 346 melanoma pathology reports from patients cared for between 2012 and 2020. They limited their investigation to those diagnosed with biopsy-confirmed melanoma and analyzed the number of melanomas, Breslow depth, follow-up full-body skin exams, family history of melanoma, gender, insurance, and age (categorized as younger than 70 years and 70 years or older). To determine patient travel distance, they calculated the miles between the ZIP codes of the patient’s residence and the dermatology practice.
Regression analysis revealed that the . Specifically, among patients diagnosed with two or more melanomas, 45.0% lived more than 20 miles away and 21.3% lived less than 15 miles away; 59.6% were age 70 and older, while 40.4% were younger than age 70 (P less than .01).
No statistically significant association was observed between travel distance and Breslow depth or follow-up full-body skin exams within 1 year following diagnosis.
In other findings, among patients who lived more than 20 miles from the practice, those aged 70 and older were diagnosed with 0.56 more melanomas than patients between the ages of 58 and 70 (P = .00003), and 0.31 more melanomas than patients who lived 15-20 miles away (P = .014). No statistically significant differences in the number of melanomas diagnosed were observed between patients in either age group who lived fewer than 15 miles from the office.
“We were surprised that the combination of age and patient distance to diagnosing dermatology provider was such a powerful predictor of the number of diagnosed melanomas,” Ms. Parisi said. “It’s probably due to less mobility among older patients living in more remote areas, and it puts them at higher risk of multiple melanomas. This was something we haven’t seen in the dermatology literature.”
She and her coauthors acknowledged that the limited sampling of patients from a single practice “may not generalize across all urban and rural settings, and results must be considered preliminary,” they wrote. However, “our findings reveal an important vulnerability among older patients in nonurban areas, and efforts to improve access to melanoma diagnosis should be concentrated on this geodemographic segment.”
Nikolai Klebanov, MD, of the department of dermatology at Massachusetts General Hospital, Boston, who was asked to comment on the study, described what was addressed in the study as a “timely and an important topic.”
In an interview, he said, “there is less access to dermatologists and other medical specialists outside of large metropolitan and suburban areas,” and there are other health disparities affecting people living in rural or more underserved areas, which, he added, “also became exacerbated by the COVID-19 pandemic.”
For future studies on this topic, Dr. Klebanov said that he would be interested to see diagnoses measured per person-year rather than the total number of melanomas diagnosed. “More elderly patients may also be those who have ‘stuck with the practice’ for longer, and had a longer follow-up that gives more time to catch more melanomas,” he said.
“Adjusting for median income using ZIP codes could also help adjust for socioeconomic status, which would help with external validity of the study. Income relationships to geography are not the same in all cities; some have wealthy suburbs within 20 miles, while some have more underserved and rural areas at that distance.”
Neither the researchers nor Dr. Klebanov reported having financial disclosures.
FROM JAMA DERMATOLOGY
Which AK treatment has the best long-term efficacy? A study reviews the data
The four results from a systemic review and meta-analysis suggest.
To date, many studies have reported that “most interventions are superior to placebo in terms of lesion clearance and improving the cosmetic image,” corresponding author Markus V. Heppt, MD, MSc, and colleagues wrote in a study published online Aug. 4, 2021, in JAMA Dermatology.
“However, most randomized clinical trials (RCTs) and meta-analyses focused on short-term outcomes that are evaluated within 3-6 months after treatment, although AK is increasingly being considered a chronic condition and reducing the incidence of cSCC [cutaneous squamous cell carcinoma] should be the ultimate goal of treatment,” they said. In addition, most treatments have been compared with placebo “and head-to-head comparisons are widely lacking, limiting the possibility to cross compare distinct active treatments. To this end, no evidence-based recommendation regarding the long-term efficacy of interventions for AK exists.”
To determine the long-term clearance rates of treatments used in adults with AK, a precursor of cSCC, Dr. Heppt, of the department of dermatology at University Hospital Erlangen (Germany), and colleagues drew from 15 randomized clinical trials that reported sustained clearance rates after at least 12 months of treatment and were published up to April 6, 2020. They conducted the review by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline and its extension for network meta-analyses (PRIMSA-NMA) and using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process to determine the certainty of the evidence for network meta-analyses.
The study population included 4,252 patients. Among 10 studies included in a network meta-analysis for the outcome of participant complete clearance, ALA-PDT showed the most favorable risk ratio profile, compared with placebo (RR, 8.06; moderate-quality evidence on GRADE), followed by imiquimod, 5% (RR, 5.98; very-low-quality evidence on GRADE); MAL-PDT (RR, 5.95; low-quality evidence on GRADE); and cryosurgery (RR, 4.76; very-low-quality evidence on GRADE).
ALA-PDT had the highest RR in the network meta-analyses for lesion-specific clearance (RR, 5.08; moderate-quality evidence on GRADE).
“Although ALA-PDT showed the most favorable RR and was ranked best among all interventions, the relative efficacy values and treatment rankings must be interpreted with caution,” because of the low certainty of evidence and few direct, head-to-head comparisons, the authors emphasized. “In particular, it remains elusive how to translate the distinct RR values into clinical relevance. We are hesitant to derive hierarchical or algorithmic treatment recommendations from our results.”
“The current meta-analysis notes that there are conflicting results in different studies,” said Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn. who was asked to comment on the study. “Sustained participant complete clearance of actinic keratoses at 12 months is used as an outcome measure, although the authors comment that prevention/reduction of squamous cell carcinoma might be the more valid outcome measure.”
In her clinical experience, Dr. Ko said that patients often have good, sustained clearance of AKs with field treatment using a topical medication like 5-fluorouracil. “Patients can also have a good result with photodynamic therapy,” she said. “The paper’s results therefore do reflect what I have seen in my own practice. I also agree with the authors that, while it is difficult to measure, a meaningful outcome for patients is reduction/prevention of squamous cell carcinoma. It would be useful to have data on which treatment of actinic keratosis is best to reduce/prevent squamous cell carcinoma.”
The authors acknowledged limitations of the study, including the fact that field-directed treatments such as imiquimod, PDT, and fluorouracil were compared with lesion-directed approaches such as cryosurgery, “which may limit the generalizability of our results.” They concluded that their analysis “provides data that might contribute to an evidence-based framework to guide the selection of interventions for AK with proven long-term efficacy and sustained AK clearance.”
The analysis did not include data on tirbanibulin, a first-in-class dual Src kinase and tubulin polymerization inhibitor that was approved by the FDA for the topical treatment of AKs on the face or scalp in December 2020.
Dr. Heppt disclosed that he has been a member of the advisory boards of Almirall Hermal and Sanofi-Aventis and has received speaker’s honoraria from Galderma and Biofrontera. Many of his coauthors also reported having relevant financial disclosures. Dr. Ko reported having no relevant disclosures.
The four results from a systemic review and meta-analysis suggest.
To date, many studies have reported that “most interventions are superior to placebo in terms of lesion clearance and improving the cosmetic image,” corresponding author Markus V. Heppt, MD, MSc, and colleagues wrote in a study published online Aug. 4, 2021, in JAMA Dermatology.
“However, most randomized clinical trials (RCTs) and meta-analyses focused on short-term outcomes that are evaluated within 3-6 months after treatment, although AK is increasingly being considered a chronic condition and reducing the incidence of cSCC [cutaneous squamous cell carcinoma] should be the ultimate goal of treatment,” they said. In addition, most treatments have been compared with placebo “and head-to-head comparisons are widely lacking, limiting the possibility to cross compare distinct active treatments. To this end, no evidence-based recommendation regarding the long-term efficacy of interventions for AK exists.”
To determine the long-term clearance rates of treatments used in adults with AK, a precursor of cSCC, Dr. Heppt, of the department of dermatology at University Hospital Erlangen (Germany), and colleagues drew from 15 randomized clinical trials that reported sustained clearance rates after at least 12 months of treatment and were published up to April 6, 2020. They conducted the review by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline and its extension for network meta-analyses (PRIMSA-NMA) and using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process to determine the certainty of the evidence for network meta-analyses.
The study population included 4,252 patients. Among 10 studies included in a network meta-analysis for the outcome of participant complete clearance, ALA-PDT showed the most favorable risk ratio profile, compared with placebo (RR, 8.06; moderate-quality evidence on GRADE), followed by imiquimod, 5% (RR, 5.98; very-low-quality evidence on GRADE); MAL-PDT (RR, 5.95; low-quality evidence on GRADE); and cryosurgery (RR, 4.76; very-low-quality evidence on GRADE).
ALA-PDT had the highest RR in the network meta-analyses for lesion-specific clearance (RR, 5.08; moderate-quality evidence on GRADE).
“Although ALA-PDT showed the most favorable RR and was ranked best among all interventions, the relative efficacy values and treatment rankings must be interpreted with caution,” because of the low certainty of evidence and few direct, head-to-head comparisons, the authors emphasized. “In particular, it remains elusive how to translate the distinct RR values into clinical relevance. We are hesitant to derive hierarchical or algorithmic treatment recommendations from our results.”
“The current meta-analysis notes that there are conflicting results in different studies,” said Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn. who was asked to comment on the study. “Sustained participant complete clearance of actinic keratoses at 12 months is used as an outcome measure, although the authors comment that prevention/reduction of squamous cell carcinoma might be the more valid outcome measure.”
In her clinical experience, Dr. Ko said that patients often have good, sustained clearance of AKs with field treatment using a topical medication like 5-fluorouracil. “Patients can also have a good result with photodynamic therapy,” she said. “The paper’s results therefore do reflect what I have seen in my own practice. I also agree with the authors that, while it is difficult to measure, a meaningful outcome for patients is reduction/prevention of squamous cell carcinoma. It would be useful to have data on which treatment of actinic keratosis is best to reduce/prevent squamous cell carcinoma.”
The authors acknowledged limitations of the study, including the fact that field-directed treatments such as imiquimod, PDT, and fluorouracil were compared with lesion-directed approaches such as cryosurgery, “which may limit the generalizability of our results.” They concluded that their analysis “provides data that might contribute to an evidence-based framework to guide the selection of interventions for AK with proven long-term efficacy and sustained AK clearance.”
The analysis did not include data on tirbanibulin, a first-in-class dual Src kinase and tubulin polymerization inhibitor that was approved by the FDA for the topical treatment of AKs on the face or scalp in December 2020.
Dr. Heppt disclosed that he has been a member of the advisory boards of Almirall Hermal and Sanofi-Aventis and has received speaker’s honoraria from Galderma and Biofrontera. Many of his coauthors also reported having relevant financial disclosures. Dr. Ko reported having no relevant disclosures.
The four results from a systemic review and meta-analysis suggest.
To date, many studies have reported that “most interventions are superior to placebo in terms of lesion clearance and improving the cosmetic image,” corresponding author Markus V. Heppt, MD, MSc, and colleagues wrote in a study published online Aug. 4, 2021, in JAMA Dermatology.
“However, most randomized clinical trials (RCTs) and meta-analyses focused on short-term outcomes that are evaluated within 3-6 months after treatment, although AK is increasingly being considered a chronic condition and reducing the incidence of cSCC [cutaneous squamous cell carcinoma] should be the ultimate goal of treatment,” they said. In addition, most treatments have been compared with placebo “and head-to-head comparisons are widely lacking, limiting the possibility to cross compare distinct active treatments. To this end, no evidence-based recommendation regarding the long-term efficacy of interventions for AK exists.”
To determine the long-term clearance rates of treatments used in adults with AK, a precursor of cSCC, Dr. Heppt, of the department of dermatology at University Hospital Erlangen (Germany), and colleagues drew from 15 randomized clinical trials that reported sustained clearance rates after at least 12 months of treatment and were published up to April 6, 2020. They conducted the review by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline and its extension for network meta-analyses (PRIMSA-NMA) and using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process to determine the certainty of the evidence for network meta-analyses.
The study population included 4,252 patients. Among 10 studies included in a network meta-analysis for the outcome of participant complete clearance, ALA-PDT showed the most favorable risk ratio profile, compared with placebo (RR, 8.06; moderate-quality evidence on GRADE), followed by imiquimod, 5% (RR, 5.98; very-low-quality evidence on GRADE); MAL-PDT (RR, 5.95; low-quality evidence on GRADE); and cryosurgery (RR, 4.76; very-low-quality evidence on GRADE).
ALA-PDT had the highest RR in the network meta-analyses for lesion-specific clearance (RR, 5.08; moderate-quality evidence on GRADE).
“Although ALA-PDT showed the most favorable RR and was ranked best among all interventions, the relative efficacy values and treatment rankings must be interpreted with caution,” because of the low certainty of evidence and few direct, head-to-head comparisons, the authors emphasized. “In particular, it remains elusive how to translate the distinct RR values into clinical relevance. We are hesitant to derive hierarchical or algorithmic treatment recommendations from our results.”
“The current meta-analysis notes that there are conflicting results in different studies,” said Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn. who was asked to comment on the study. “Sustained participant complete clearance of actinic keratoses at 12 months is used as an outcome measure, although the authors comment that prevention/reduction of squamous cell carcinoma might be the more valid outcome measure.”
In her clinical experience, Dr. Ko said that patients often have good, sustained clearance of AKs with field treatment using a topical medication like 5-fluorouracil. “Patients can also have a good result with photodynamic therapy,” she said. “The paper’s results therefore do reflect what I have seen in my own practice. I also agree with the authors that, while it is difficult to measure, a meaningful outcome for patients is reduction/prevention of squamous cell carcinoma. It would be useful to have data on which treatment of actinic keratosis is best to reduce/prevent squamous cell carcinoma.”
The authors acknowledged limitations of the study, including the fact that field-directed treatments such as imiquimod, PDT, and fluorouracil were compared with lesion-directed approaches such as cryosurgery, “which may limit the generalizability of our results.” They concluded that their analysis “provides data that might contribute to an evidence-based framework to guide the selection of interventions for AK with proven long-term efficacy and sustained AK clearance.”
The analysis did not include data on tirbanibulin, a first-in-class dual Src kinase and tubulin polymerization inhibitor that was approved by the FDA for the topical treatment of AKs on the face or scalp in December 2020.
Dr. Heppt disclosed that he has been a member of the advisory boards of Almirall Hermal and Sanofi-Aventis and has received speaker’s honoraria from Galderma and Biofrontera. Many of his coauthors also reported having relevant financial disclosures. Dr. Ko reported having no relevant disclosures.
FROM JAMA DERMATOLOGY