Results of a phase 2 trial suggest an investigational agent may improve upon standard care for acquired thrombotic thrombocytopenic purpura (aTTP).

The agent, caplacizumab, is an anti-von Willebrand factor, humanized, single-variable-domain immunoglobulin that works by inhibiting the interaction between ultralarge von Willebrand factor multimers and platelets.

In the phase 2 TITAN trial, caplacizumab plus standard care induced a faster resolution of aTTP episodes when compared to placebo plus standard care. However, caplacizumab was also associated with a higher risk of bleeding.

Flora Peyvandi, MD, PhD, of the University of Milan in Italy, and her colleagues reported these results in The New England Journal of Medicine. The study was supported by Ablynx, the company developing caplacizumab.

“Caplacizumab has the potential to become an important new component in the standard of care for patients with acquired TTP,” Dr Peyvandi said. “The results from the phase 2 TITAN study showed that caplacizumab acts quickly to control the critical acute phase of the disease and protects patients until immunosuppressive treatments take effect.”

TITAN was a single-blinded, randomized, placebo-controlled study conducted at 56 centers around the world. The trial included 75 aTTP patients who were randomized to caplacizumab (n=36) or placebo (n=39), with all patients receiving the current standard of care (daily plasma exchange and immunosuppressive therapy).

Patients in the caplacizumab arm immediately received an intravenous bolus dose of caplacizumab at 10 mg and then a 10 mg subcutaneous dose of the drug daily until 30 days had elapsed after the final plasma exchange. Patients in the control arm received placebo at the same time points.

Response, recurrence, and relapse

The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).

Among the 69 patients who had not undergone a plasma-exchange session before enrollment, the median time to response was 3.0 days in the caplacizumab arm and 4.9 days in the placebo arm.

Among the 6 patients who did undergo a plasma-exchange session before enrollment, the median time to a response was 2.4 days in the caplacizumab arm and 4.3 days in the placebo arm.

The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.

One of the study’s secondary endpoints was exacerbation, which was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.

There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively.

Another secondary endpoint was relapse, which was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.

There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. The investigators noted that 7 of the 8 patients had ADAMTS13 activity that remained below 10%, which suggests unresolved autoimmune activity.

Adverse events

There were 541 adverse events (AEs) in 34 of the 35 evaluable patients receiving caplacizumab (97%) and 522 AEs in all 37 evaluable patients receiving placebo (100%). TTP exacerbations and relapses were not included as AEs.

The rate of AEs thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. And the rate of serious AEs was 37% and 32%, respectively.

The rate of bleeding-related AEs was 54% in the caplacizumab arm and 38% in the placebo arm. Of the 101 bleeding-related AEs, 84 (83%) were reported as mild, 14 (14%) as moderate, and 3 (3%) as severe.

There were no deaths in the caplacizumab arm and 2 in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.

Caplacizumab development

The results of this trial will serve as the basis for filing for conditional approval of caplacizumab in Europe in the first half of 2017, according to Ablynx. The company is planning to file in the US in 2018.

Ablynx has started a phase 3 trial of caplacizumab known as the HERCULES study. In this double-blind, placebo-controlled study, investigators are evaluating the safety and efficacy of caplacizumab, in conjunction with the standard of care, in patients with aTTP.

The study is expected to enroll 92 patients at clinical sites across 17 countries. Recruitment is expected to be complete by the end of 2017.

Results of a phase 2 trial suggest an investigational agent may improve upon standard care for acquired thrombotic thrombocytopenic purpura (aTTP).

The agent, caplacizumab, is an anti-von Willebrand factor, humanized, single-variable-domain immunoglobulin that works by inhibiting the interaction between ultralarge von Willebrand factor multimers and platelets.

In the phase 2 TITAN trial, caplacizumab plus standard care induced a faster resolution of aTTP episodes when compared to placebo plus standard care. However, caplacizumab was also associated with a higher risk of bleeding.

Flora Peyvandi, MD, PhD, of the University of Milan in Italy, and her colleagues reported these results in The New England Journal of Medicine. The study was supported by Ablynx, the company developing caplacizumab.

“Caplacizumab has the potential to become an important new component in the standard of care for patients with acquired TTP,” Dr Peyvandi said. “The results from the phase 2 TITAN study showed that caplacizumab acts quickly to control the critical acute phase of the disease and protects patients until immunosuppressive treatments take effect.”

TITAN was a single-blinded, randomized, placebo-controlled study conducted at 56 centers around the world. The trial included 75 aTTP patients who were randomized to caplacizumab (n=36) or placebo (n=39), with all patients receiving the current standard of care (daily plasma exchange and immunosuppressive therapy).

Patients in the caplacizumab arm immediately received an intravenous bolus dose of caplacizumab at 10 mg and then a 10 mg subcutaneous dose of the drug daily until 30 days had elapsed after the final plasma exchange. Patients in the control arm received placebo at the same time points.

Response, recurrence, and relapse

The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).

Among the 69 patients who had not undergone a plasma-exchange session before enrollment, the median time to response was 3.0 days in the caplacizumab arm and 4.9 days in the placebo arm.

Among the 6 patients who did undergo a plasma-exchange session before enrollment, the median time to a response was 2.4 days in the caplacizumab arm and 4.3 days in the placebo arm.

The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.

One of the study’s secondary endpoints was exacerbation, which was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.

There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively.

Another secondary endpoint was relapse, which was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.

There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. The investigators noted that 7 of the 8 patients had ADAMTS13 activity that remained below 10%, which suggests unresolved autoimmune activity.

Adverse events

There were 541 adverse events (AEs) in 34 of the 35 evaluable patients receiving caplacizumab (97%) and 522 AEs in all 37 evaluable patients receiving placebo (100%). TTP exacerbations and relapses were not included as AEs.

The rate of AEs thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. And the rate of serious AEs was 37% and 32%, respectively.

The rate of bleeding-related AEs was 54% in the caplacizumab arm and 38% in the placebo arm. Of the 101 bleeding-related AEs, 84 (83%) were reported as mild, 14 (14%) as moderate, and 3 (3%) as severe.

There were no deaths in the caplacizumab arm and 2 in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.

Caplacizumab development

The results of this trial will serve as the basis for filing for conditional approval of caplacizumab in Europe in the first half of 2017, according to Ablynx. The company is planning to file in the US in 2018.

Ablynx has started a phase 3 trial of caplacizumab known as the HERCULES study. In this double-blind, placebo-controlled study, investigators are evaluating the safety and efficacy of caplacizumab, in conjunction with the standard of care, in patients with aTTP.

The study is expected to enroll 92 patients at clinical sites across 17 countries. Recruitment is expected to be complete by the end of 2017.

Results of a phase 2 trial suggest an investigational agent may improve upon standard care for acquired thrombotic thrombocytopenic purpura (aTTP).

The agent, caplacizumab, is an anti-von Willebrand factor, humanized, single-variable-domain immunoglobulin that works by inhibiting the interaction between ultralarge von Willebrand factor multimers and platelets.

In the phase 2 TITAN trial, caplacizumab plus standard care induced a faster resolution of aTTP episodes when compared to placebo plus standard care. However, caplacizumab was also associated with a higher risk of bleeding.

Flora Peyvandi, MD, PhD, of the University of Milan in Italy, and her colleagues reported these results in The New England Journal of Medicine. The study was supported by Ablynx, the company developing caplacizumab.

“Caplacizumab has the potential to become an important new component in the standard of care for patients with acquired TTP,” Dr Peyvandi said. “The results from the phase 2 TITAN study showed that caplacizumab acts quickly to control the critical acute phase of the disease and protects patients until immunosuppressive treatments take effect.”

TITAN was a single-blinded, randomized, placebo-controlled study conducted at 56 centers around the world. The trial included 75 aTTP patients who were randomized to caplacizumab (n=36) or placebo (n=39), with all patients receiving the current standard of care (daily plasma exchange and immunosuppressive therapy).

Patients in the caplacizumab arm immediately received an intravenous bolus dose of caplacizumab at 10 mg and then a 10 mg subcutaneous dose of the drug daily until 30 days had elapsed after the final plasma exchange. Patients in the control arm received placebo at the same time points.

Response, recurrence, and relapse

The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).

Among the 69 patients who had not undergone a plasma-exchange session before enrollment, the median time to response was 3.0 days in the caplacizumab arm and 4.9 days in the placebo arm.

Among the 6 patients who did undergo a plasma-exchange session before enrollment, the median time to a response was 2.4 days in the caplacizumab arm and 4.3 days in the placebo arm.

The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.

One of the study’s secondary endpoints was exacerbation, which was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.

There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively.

Another secondary endpoint was relapse, which was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.

There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. The investigators noted that 7 of the 8 patients had ADAMTS13 activity that remained below 10%, which suggests unresolved autoimmune activity.

Adverse events

There were 541 adverse events (AEs) in 34 of the 35 evaluable patients receiving caplacizumab (97%) and 522 AEs in all 37 evaluable patients receiving placebo (100%). TTP exacerbations and relapses were not included as AEs.

The rate of AEs thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. And the rate of serious AEs was 37% and 32%, respectively.

The rate of bleeding-related AEs was 54% in the caplacizumab arm and 38% in the placebo arm. Of the 101 bleeding-related AEs, 84 (83%) were reported as mild, 14 (14%) as moderate, and 3 (3%) as severe.

There were no deaths in the caplacizumab arm and 2 in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.

Caplacizumab development

The results of this trial will serve as the basis for filing for conditional approval of caplacizumab in Europe in the first half of 2017, according to Ablynx. The company is planning to file in the US in 2018.

Ablynx has started a phase 3 trial of caplacizumab known as the HERCULES study. In this double-blind, placebo-controlled study, investigators are evaluating the safety and efficacy of caplacizumab, in conjunction with the standard of care, in patients with aTTP.

The study is expected to enroll 92 patients at clinical sites across 17 countries. Recruitment is expected to be complete by the end of 2017.

Children reading

Pediatric acute lymphoblastic leukemia (ALL) patients treated with chemotherapy alone are at risk for attention and learning problems that persist after treatment ends, according to a study published in the Journal of Clinical Oncology.

Researchers said this study is the largest assessment to date of neurocognitive outcomes in pediatric ALL survivors treated with intensive chemotherapy alone rather than in combination with cranial radiation.

“This is an important contribution to the literature because the smaller size and design of previous studies made examining the impact of treatment difficult,” said study author Lisa Jacola, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“The findings underscore the need for neurocognitive and academic screening to be included as part of routine survivorship care for all pediatric ALL survivors.”

The study included patients enrolled in the St. Jude Total Therapy Study XV. They underwent neurocognitive assessments at the beginning of induction (n=142), end of maintenance (n=243), and 2 years after completing treatment (n=211).

The subjects completed standardized tests of overall intelligence, attention, learning, and academic performance. In addition, parents and other caregivers rated the subjects’ attention, learning, and behavior.

Two years after treatment completion, subjects performed as expected for their age (compared to national data) on measures of overall intelligence, learning, and memory. However, study subjects had significant attention deficits and a significantly greater frequency of learning problems (all P≤0.005).

The risk of such problems was greatest for survivors who were less than 5 years old when diagnosed with ALL and for those who received more intensive chemotherapy.

Specifically, the younger subjects had a greater risk of difficulties with attention, learning, working memory, and processing speed (all P≤0.05). And subjects who received higher-intensity, CNS-directed chemotherapy had a greater risk of difficulties in attention, processing speed, and academics (all P≤0.01).

Researchers also found that subjects with attention problems at the end of therapy had lower academic scores 2 years later (all P≤0.05).

“These findings provide additional evidence that neurocognitive functioning has improved in survivors of childhood ALL since cranial irradiation was replaced with intensified chemotherapy,” Dr Jacola said.

“But we also show these young people are at an elevated risk for attention problems that have real-world consequences, particularly for learning and school performance. Attention is a building block for learning, and, in this study, attention difficulties predicted academic problems later. If we know attention problems seen at the end of therapy continue and contribute to academic problems, then our goal is to intervene earlier to reduce or prevent such difficulties.”

Children reading

Pediatric acute lymphoblastic leukemia (ALL) patients treated with chemotherapy alone are at risk for attention and learning problems that persist after treatment ends, according to a study published in the Journal of Clinical Oncology.

Researchers said this study is the largest assessment to date of neurocognitive outcomes in pediatric ALL survivors treated with intensive chemotherapy alone rather than in combination with cranial radiation.

“This is an important contribution to the literature because the smaller size and design of previous studies made examining the impact of treatment difficult,” said study author Lisa Jacola, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“The findings underscore the need for neurocognitive and academic screening to be included as part of routine survivorship care for all pediatric ALL survivors.”

The study included patients enrolled in the St. Jude Total Therapy Study XV. They underwent neurocognitive assessments at the beginning of induction (n=142), end of maintenance (n=243), and 2 years after completing treatment (n=211).

The subjects completed standardized tests of overall intelligence, attention, learning, and academic performance. In addition, parents and other caregivers rated the subjects’ attention, learning, and behavior.

Two years after treatment completion, subjects performed as expected for their age (compared to national data) on measures of overall intelligence, learning, and memory. However, study subjects had significant attention deficits and a significantly greater frequency of learning problems (all P≤0.005).

The risk of such problems was greatest for survivors who were less than 5 years old when diagnosed with ALL and for those who received more intensive chemotherapy.

Specifically, the younger subjects had a greater risk of difficulties with attention, learning, working memory, and processing speed (all P≤0.05). And subjects who received higher-intensity, CNS-directed chemotherapy had a greater risk of difficulties in attention, processing speed, and academics (all P≤0.01).

Researchers also found that subjects with attention problems at the end of therapy had lower academic scores 2 years later (all P≤0.05).

“These findings provide additional evidence that neurocognitive functioning has improved in survivors of childhood ALL since cranial irradiation was replaced with intensified chemotherapy,” Dr Jacola said.

“But we also show these young people are at an elevated risk for attention problems that have real-world consequences, particularly for learning and school performance. Attention is a building block for learning, and, in this study, attention difficulties predicted academic problems later. If we know attention problems seen at the end of therapy continue and contribute to academic problems, then our goal is to intervene earlier to reduce or prevent such difficulties.”

Children reading

Pediatric acute lymphoblastic leukemia (ALL) patients treated with chemotherapy alone are at risk for attention and learning problems that persist after treatment ends, according to a study published in the Journal of Clinical Oncology.

Researchers said this study is the largest assessment to date of neurocognitive outcomes in pediatric ALL survivors treated with intensive chemotherapy alone rather than in combination with cranial radiation.

“This is an important contribution to the literature because the smaller size and design of previous studies made examining the impact of treatment difficult,” said study author Lisa Jacola, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“The findings underscore the need for neurocognitive and academic screening to be included as part of routine survivorship care for all pediatric ALL survivors.”

The study included patients enrolled in the St. Jude Total Therapy Study XV. They underwent neurocognitive assessments at the beginning of induction (n=142), end of maintenance (n=243), and 2 years after completing treatment (n=211).

The subjects completed standardized tests of overall intelligence, attention, learning, and academic performance. In addition, parents and other caregivers rated the subjects’ attention, learning, and behavior.

Two years after treatment completion, subjects performed as expected for their age (compared to national data) on measures of overall intelligence, learning, and memory. However, study subjects had significant attention deficits and a significantly greater frequency of learning problems (all P≤0.005).

The risk of such problems was greatest for survivors who were less than 5 years old when diagnosed with ALL and for those who received more intensive chemotherapy.

Specifically, the younger subjects had a greater risk of difficulties with attention, learning, working memory, and processing speed (all P≤0.05). And subjects who received higher-intensity, CNS-directed chemotherapy had a greater risk of difficulties in attention, processing speed, and academics (all P≤0.01).

Researchers also found that subjects with attention problems at the end of therapy had lower academic scores 2 years later (all P≤0.05).

“These findings provide additional evidence that neurocognitive functioning has improved in survivors of childhood ALL since cranial irradiation was replaced with intensified chemotherapy,” Dr Jacola said.

“But we also show these young people are at an elevated risk for attention problems that have real-world consequences, particularly for learning and school performance. Attention is a building block for learning, and, in this study, attention difficulties predicted academic problems later. If we know attention problems seen at the end of therapy continue and contribute to academic problems, then our goal is to intervene earlier to reduce or prevent such difficulties.”

Endothelial cells

Image courtesy of NIH

Low doses of iron can modify the vascular endothelium and induce a DNA-damage response, researchers have reported in PLOS ONE.

The team observed these phenomena in vitro and said the results must be confirmed via additional research.

However, the findings suggest a need to assess the amount of iron given in standard treatments and the effects this may have on the body, according to Claire Shovlin, PhD, of Imperial College London in the UK.

Dr Shovlin and her colleagues studied human endothelial cells, adding either placebo or an iron solution of 10 micromolar, which is a similar concentration to that seen in the blood after taking an iron tablet.

Within 10 minutes, cells treated with the iron solution had activated DNA repair systems, and these were still activated 6 hours later.

“We already knew that iron could be damaging to cells in very high doses,” Dr Shovlin said. “However, in this study, we found that when we applied the kinds of levels of iron you would find in the bloodstream after taking an iron tablet, this also seemed to be able to trigger cell damage—at least in the laboratory. In other words, cells seem more sensitive to iron than we previously thought.”

“This is very early stage research, and we need more work to confirm these findings and investigate what effects this may have on the body. We are still not sure how these laboratory findings translate to blood vessels in the body.”

“However, this study helps to open the conversation about how much iron people take. At the moment, each standard iron tablet contains almost 10 times the amount of iron men are recommended to eat each day, and these dosages haven’t changed for more than 50 years. This research suggests we may need to think more carefully about how much iron we give to people, and try and tailor the dose to the patient.”

Dr Shovlin and her colleagues initially started researching this area after finding that a small proportion of people using iron tablets for hereditary hemorrhagic telangiectasia, which causes abnormalities in the blood vessels, reported their nose bleeds worsened after iron treatment.

Endothelial cells

Image courtesy of NIH

Low doses of iron can modify the vascular endothelium and induce a DNA-damage response, researchers have reported in PLOS ONE.

The team observed these phenomena in vitro and said the results must be confirmed via additional research.

However, the findings suggest a need to assess the amount of iron given in standard treatments and the effects this may have on the body, according to Claire Shovlin, PhD, of Imperial College London in the UK.

Dr Shovlin and her colleagues studied human endothelial cells, adding either placebo or an iron solution of 10 micromolar, which is a similar concentration to that seen in the blood after taking an iron tablet.

Within 10 minutes, cells treated with the iron solution had activated DNA repair systems, and these were still activated 6 hours later.

“We already knew that iron could be damaging to cells in very high doses,” Dr Shovlin said. “However, in this study, we found that when we applied the kinds of levels of iron you would find in the bloodstream after taking an iron tablet, this also seemed to be able to trigger cell damage—at least in the laboratory. In other words, cells seem more sensitive to iron than we previously thought.”

“This is very early stage research, and we need more work to confirm these findings and investigate what effects this may have on the body. We are still not sure how these laboratory findings translate to blood vessels in the body.”

“However, this study helps to open the conversation about how much iron people take. At the moment, each standard iron tablet contains almost 10 times the amount of iron men are recommended to eat each day, and these dosages haven’t changed for more than 50 years. This research suggests we may need to think more carefully about how much iron we give to people, and try and tailor the dose to the patient.”

Dr Shovlin and her colleagues initially started researching this area after finding that a small proportion of people using iron tablets for hereditary hemorrhagic telangiectasia, which causes abnormalities in the blood vessels, reported their nose bleeds worsened after iron treatment.

Endothelial cells

Image courtesy of NIH

Low doses of iron can modify the vascular endothelium and induce a DNA-damage response, researchers have reported in PLOS ONE.

The team observed these phenomena in vitro and said the results must be confirmed via additional research.

However, the findings suggest a need to assess the amount of iron given in standard treatments and the effects this may have on the body, according to Claire Shovlin, PhD, of Imperial College London in the UK.

Dr Shovlin and her colleagues studied human endothelial cells, adding either placebo or an iron solution of 10 micromolar, which is a similar concentration to that seen in the blood after taking an iron tablet.

Within 10 minutes, cells treated with the iron solution had activated DNA repair systems, and these were still activated 6 hours later.

“We already knew that iron could be damaging to cells in very high doses,” Dr Shovlin said. “However, in this study, we found that when we applied the kinds of levels of iron you would find in the bloodstream after taking an iron tablet, this also seemed to be able to trigger cell damage—at least in the laboratory. In other words, cells seem more sensitive to iron than we previously thought.”

“This is very early stage research, and we need more work to confirm these findings and investigate what effects this may have on the body. We are still not sure how these laboratory findings translate to blood vessels in the body.”

“However, this study helps to open the conversation about how much iron people take. At the moment, each standard iron tablet contains almost 10 times the amount of iron men are recommended to eat each day, and these dosages haven’t changed for more than 50 years. This research suggests we may need to think more carefully about how much iron we give to people, and try and tailor the dose to the patient.”

Dr Shovlin and her colleagues initially started researching this area after finding that a small proportion of people using iron tablets for hereditary hemorrhagic telangiectasia, which causes abnormalities in the blood vessels, reported their nose bleeds worsened after iron treatment.

It seemed like a teachable moment. My student looked on as Laura took off her shoes and showed us livid, polycyclic plaques covering the dorsum of her left foot. The way her rash looked, bordering 10 obviously fungal toenails, left little doubt about the problem.

“I’m going to guess you’re using a steroid cream,” I said.

“Could I please tell you the whole story?” said Laura, with some impatience.

“Sure,” I said. I love whole stories.

So Laura told me hers, starting with her walk through the tall grass in the summer, followed by “poison ivy” that her primary care physician treated with “a cream.”

“Did the cream have hydrocortisone in it?”

“I think so,” she said. But that didn’t work, so her doctor prescribed another cream. That one seemed to help a bit, but then the rash got redder and itchier, so she got another cream. “I think it was called clobetasol,” Laura said.

“Several years ago,” Laura went on, “you said I had toenail fungus in my nails, but I didn’t want to take pills for it because it didn’t bother me enough.”

“Maybe now would be a good time,” I said.

After I had recommended oral and topical therapy (and stopped the clobetasol!), my student and I went into my office. Like most of my students, she is headed for a career in primary care, in her case, Family Medicine.

“What do you think?” I asked her. “How does this case reflect on the state of dermatology expertise in the primary care community?” We’ve been discussing this, because Laura’s was not the first such example, just the most egregious.

My student’s eyes widened. No need to belabor the point.

“The problem is not that Laura’s primary care physician made a mistake,” I said. “I make them too, like prescribing antifungal creams for eczema and steroid creams for fungi. The problem is not noticing that you’ve made the mistake – with the evidence literally staring you in the face – and then either fixing it, or else consulting someone else who can help you fix it.”

“I’m going to do a better job!” said my student, with feeling.

Perhaps she will. At least she will graduate medical school having learned that there is such a thing as nummular eczema and been told that not every round rash is a fungus. As with almost every 4th-year student who’s taken my elective for the last 35 years, she had little dermatology exposure until now beyond a couple of PowerPoint shows of exotic diseases. I had none either back in school, when dinosaurs roamed the earth.

After I graduated, my prestigious pediatric residency taught me a grand total of three dermatologic facts: 1. For tinea capitis, shine a Wood’s light on the scalp; 2. For pityriasis rosea, shine a Wood’s light on the body; and 3. If a groin wash involves the inguinal fold, it’s a yeast infection. I learned a lot, didn’t I?

Reflecting on Lesson #1, Trichophyton tonsurans, which doesn’t fluoresce, has predominated for half a century (and 90% of the time, the problem is seborrhea anyway). As for #2 and #3, never mind.

Decade after decade, the patients troop in: Eczemas treated as fungi, fungi treated with steroids, itchy rashes treated with permethrin, then treated again because the itch didn’t stop, because you can’t kill bugs that aren’t there.

Clinical dermatology is not rocket science. Eczema and fungus are so common that it is hardly possible not to encounter them in daily practice. Generations of providers come and go, yet the same clinical missteps persist.

Why are the common skin problems of ordinary patients not a priority in medical education? Why do so many practitioners keep doing the same things and not get better at doing them?

Perhaps such common problems just pass under the educational radar. Maybe these diseases aren’t sexy enough, their poor outcomes not consequential enough. Maybe the shoe just doesn’t pinch hard enough on these itchy, polycyclic plaques.

My students are very young and earnest. They mean to get out into the world and do a good job. Many challenges before them, which now include crushing, mind-numbing bureaucratic demands. Can we ask that, while they are busy clicking drop-down boxes on their EHR’s and mastering genomic medicine, they also treat eczema as eczema and fungus as fungus?

One hopes so.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years.

It seemed like a teachable moment. My student looked on as Laura took off her shoes and showed us livid, polycyclic plaques covering the dorsum of her left foot. The way her rash looked, bordering 10 obviously fungal toenails, left little doubt about the problem.

“I’m going to guess you’re using a steroid cream,” I said.

“Could I please tell you the whole story?” said Laura, with some impatience.

“Sure,” I said. I love whole stories.

So Laura told me hers, starting with her walk through the tall grass in the summer, followed by “poison ivy” that her primary care physician treated with “a cream.”

“Did the cream have hydrocortisone in it?”

“I think so,” she said. But that didn’t work, so her doctor prescribed another cream. That one seemed to help a bit, but then the rash got redder and itchier, so she got another cream. “I think it was called clobetasol,” Laura said.

“Several years ago,” Laura went on, “you said I had toenail fungus in my nails, but I didn’t want to take pills for it because it didn’t bother me enough.”

“Maybe now would be a good time,” I said.

After I had recommended oral and topical therapy (and stopped the clobetasol!), my student and I went into my office. Like most of my students, she is headed for a career in primary care, in her case, Family Medicine.

“What do you think?” I asked her. “How does this case reflect on the state of dermatology expertise in the primary care community?” We’ve been discussing this, because Laura’s was not the first such example, just the most egregious.

My student’s eyes widened. No need to belabor the point.

“The problem is not that Laura’s primary care physician made a mistake,” I said. “I make them too, like prescribing antifungal creams for eczema and steroid creams for fungi. The problem is not noticing that you’ve made the mistake – with the evidence literally staring you in the face – and then either fixing it, or else consulting someone else who can help you fix it.”

“I’m going to do a better job!” said my student, with feeling.

Perhaps she will. At least she will graduate medical school having learned that there is such a thing as nummular eczema and been told that not every round rash is a fungus. As with almost every 4th-year student who’s taken my elective for the last 35 years, she had little dermatology exposure until now beyond a couple of PowerPoint shows of exotic diseases. I had none either back in school, when dinosaurs roamed the earth.

After I graduated, my prestigious pediatric residency taught me a grand total of three dermatologic facts: 1. For tinea capitis, shine a Wood’s light on the scalp; 2. For pityriasis rosea, shine a Wood’s light on the body; and 3. If a groin wash involves the inguinal fold, it’s a yeast infection. I learned a lot, didn’t I?

Reflecting on Lesson #1, Trichophyton tonsurans, which doesn’t fluoresce, has predominated for half a century (and 90% of the time, the problem is seborrhea anyway). As for #2 and #3, never mind.

Decade after decade, the patients troop in: Eczemas treated as fungi, fungi treated with steroids, itchy rashes treated with permethrin, then treated again because the itch didn’t stop, because you can’t kill bugs that aren’t there.

Clinical dermatology is not rocket science. Eczema and fungus are so common that it is hardly possible not to encounter them in daily practice. Generations of providers come and go, yet the same clinical missteps persist.

Why are the common skin problems of ordinary patients not a priority in medical education? Why do so many practitioners keep doing the same things and not get better at doing them?

Perhaps such common problems just pass under the educational radar. Maybe these diseases aren’t sexy enough, their poor outcomes not consequential enough. Maybe the shoe just doesn’t pinch hard enough on these itchy, polycyclic plaques.

My students are very young and earnest. They mean to get out into the world and do a good job. Many challenges before them, which now include crushing, mind-numbing bureaucratic demands. Can we ask that, while they are busy clicking drop-down boxes on their EHR’s and mastering genomic medicine, they also treat eczema as eczema and fungus as fungus?

One hopes so.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years.

It seemed like a teachable moment. My student looked on as Laura took off her shoes and showed us livid, polycyclic plaques covering the dorsum of her left foot. The way her rash looked, bordering 10 obviously fungal toenails, left little doubt about the problem.

“I’m going to guess you’re using a steroid cream,” I said.

“Could I please tell you the whole story?” said Laura, with some impatience.

“Sure,” I said. I love whole stories.

So Laura told me hers, starting with her walk through the tall grass in the summer, followed by “poison ivy” that her primary care physician treated with “a cream.”

“Did the cream have hydrocortisone in it?”

“I think so,” she said. But that didn’t work, so her doctor prescribed another cream. That one seemed to help a bit, but then the rash got redder and itchier, so she got another cream. “I think it was called clobetasol,” Laura said.

“Several years ago,” Laura went on, “you said I had toenail fungus in my nails, but I didn’t want to take pills for it because it didn’t bother me enough.”

“Maybe now would be a good time,” I said.

After I had recommended oral and topical therapy (and stopped the clobetasol!), my student and I went into my office. Like most of my students, she is headed for a career in primary care, in her case, Family Medicine.

“What do you think?” I asked her. “How does this case reflect on the state of dermatology expertise in the primary care community?” We’ve been discussing this, because Laura’s was not the first such example, just the most egregious.

My student’s eyes widened. No need to belabor the point.

“The problem is not that Laura’s primary care physician made a mistake,” I said. “I make them too, like prescribing antifungal creams for eczema and steroid creams for fungi. The problem is not noticing that you’ve made the mistake – with the evidence literally staring you in the face – and then either fixing it, or else consulting someone else who can help you fix it.”

“I’m going to do a better job!” said my student, with feeling.

Perhaps she will. At least she will graduate medical school having learned that there is such a thing as nummular eczema and been told that not every round rash is a fungus. As with almost every 4th-year student who’s taken my elective for the last 35 years, she had little dermatology exposure until now beyond a couple of PowerPoint shows of exotic diseases. I had none either back in school, when dinosaurs roamed the earth.

After I graduated, my prestigious pediatric residency taught me a grand total of three dermatologic facts: 1. For tinea capitis, shine a Wood’s light on the scalp; 2. For pityriasis rosea, shine a Wood’s light on the body; and 3. If a groin wash involves the inguinal fold, it’s a yeast infection. I learned a lot, didn’t I?

Reflecting on Lesson #1, Trichophyton tonsurans, which doesn’t fluoresce, has predominated for half a century (and 90% of the time, the problem is seborrhea anyway). As for #2 and #3, never mind.

Decade after decade, the patients troop in: Eczemas treated as fungi, fungi treated with steroids, itchy rashes treated with permethrin, then treated again because the itch didn’t stop, because you can’t kill bugs that aren’t there.

Clinical dermatology is not rocket science. Eczema and fungus are so common that it is hardly possible not to encounter them in daily practice. Generations of providers come and go, yet the same clinical missteps persist.

Why are the common skin problems of ordinary patients not a priority in medical education? Why do so many practitioners keep doing the same things and not get better at doing them?

Perhaps such common problems just pass under the educational radar. Maybe these diseases aren’t sexy enough, their poor outcomes not consequential enough. Maybe the shoe just doesn’t pinch hard enough on these itchy, polycyclic plaques.

My students are very young and earnest. They mean to get out into the world and do a good job. Many challenges before them, which now include crushing, mind-numbing bureaucratic demands. Can we ask that, while they are busy clicking drop-down boxes on their EHR’s and mastering genomic medicine, they also treat eczema as eczema and fungus as fungus?

One hopes so.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years.

Patients aged 50 and older with recent active asthma are at elevated risk of abdominal aortic aneurysm and aneurysm rupture, according to new research.

A common inflammatory pathway between asthma and AAA, first observed nearly a decade ago in mice, is thought to be responsible.

The new findings, published online Feb. 11 in Arteriosclerosis, Thrombosis, and Vascular Biology (Arterioscler Thromb Vasc Biol. 2016. doi: 10.1161/ATVBAHA.115.306497) support the association in humans.

©Dr. Cong-Lin Liu

In a news release accompanying the findings, lead study author Guo-Ping Shi, ScD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, said that the findings had clear clinical implications for older patients with a recent asthma diagnosis. Such patients, particularly older men, “should be checked for signs” of abdominal aortic aneurysm, Dr. Shi said.*

For their research, Dr. Shi, along with colleagues at Zhengzhou (China) University, used data from a large Danish population-based cohort of nearly 16,000 patients (81% men) with AAA between 1996 and 2012, of which about 4,500 patients had rupture. They also looked at data from a comparison cohort of patients with and without AAA from a slightly larger population-based vascular screening trial of men in Denmark.

The investigators showed that hospital diagnosis of asthma within the previous year (n = 514) was associated with significantly higher risk of hospital admission with AAA rupture (n = 146) both before and after adjustment for AAA comorbidities (adjusted odds ratio 1.51-2.06). Higher risk of rupture also was seen for patients filling prescriptions for bronchodilators within the previous 3 months (aOR = 1.10-1.31), and for patients prescribed anti-asthma drugs (aOR OR = 1.09-1.48), which were seen as indicative of an outpatient asthma diagnosis.

“A hospital diagnosis of asthma or a recently filled prescription of an anti-asthmatic drug is associated with an increased risk of admission with rAAA compared with admission with intact AAA, both before and after adjusting for AAA comorbidities and relevant medications,” the researchers wrote in their analysis.

Moreover, “an asthma diagnosis or the use of bronchodilators or other anti-asthmatic drug prescriptions closer to the date of admission with AAA correlated directly with a higher risk of aortic rupture. The results remained robust after adjusting for a wide range of relevant possible confounders,” the researchers wrote.

In the cohort of patients from the vascular screening study, which included age-matched controls without AAA, asthma (measured by recent anti-asthmatic medication use) was seen associated with a significantly elevated risk of AAA before (OR = 1.45) and after adjustment for smoking (OR = 1.45) or other risk factors (OR = 1.46). This does not refer to rupture but just AAA.

Dr. Shi and colleagues noted that the AAA cohort lacked sufficient information on cigarette smoking, a known risk factor for AAA and AAA rupture, to preclude the possibility of confounding; however, the second all-male cohort did have extensive data on smoking, “and the risk of AAA among patients with asthma remained 45% higher than that of patients with nonasthma” even after adjustment.

The researchers hypothesized that an inflammatory response characterized by elevated immunoglobulin E may be the link between AAA pathogenesis and asthma, and that other allergic inflammatory diseases, including atopic dermatitis, allergic rhinitis, and some ocular allergic diseases, could potentially carry risks for AAA formation and rupture. Dr. Shi and colleagues previously investigated the IgE and aneurysm link in animal studies.

“The results have implications for the development of much needed advances in the prevention, screening criteria, and treatment of AAA, common conditions for which we currently lack sufficiently effective approaches,” the investigators wrote.

The Chinese, Danish, and U.S. governments sponsored the study. The investigators disclosed no conflicts of interest.

*CORRECTION 8/12/2020: Dr. Shi's credential was misstated in the original version on this article and has been corrected to ScD.

Patients aged 50 and older with recent active asthma are at elevated risk of abdominal aortic aneurysm and aneurysm rupture, according to new research.

A common inflammatory pathway between asthma and AAA, first observed nearly a decade ago in mice, is thought to be responsible.

The new findings, published online Feb. 11 in Arteriosclerosis, Thrombosis, and Vascular Biology (Arterioscler Thromb Vasc Biol. 2016. doi: 10.1161/ATVBAHA.115.306497) support the association in humans.

©Dr. Cong-Lin Liu

In a news release accompanying the findings, lead study author Guo-Ping Shi, ScD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, said that the findings had clear clinical implications for older patients with a recent asthma diagnosis. Such patients, particularly older men, “should be checked for signs” of abdominal aortic aneurysm, Dr. Shi said.*

For their research, Dr. Shi, along with colleagues at Zhengzhou (China) University, used data from a large Danish population-based cohort of nearly 16,000 patients (81% men) with AAA between 1996 and 2012, of which about 4,500 patients had rupture. They also looked at data from a comparison cohort of patients with and without AAA from a slightly larger population-based vascular screening trial of men in Denmark.

The investigators showed that hospital diagnosis of asthma within the previous year (n = 514) was associated with significantly higher risk of hospital admission with AAA rupture (n = 146) both before and after adjustment for AAA comorbidities (adjusted odds ratio 1.51-2.06). Higher risk of rupture also was seen for patients filling prescriptions for bronchodilators within the previous 3 months (aOR = 1.10-1.31), and for patients prescribed anti-asthma drugs (aOR OR = 1.09-1.48), which were seen as indicative of an outpatient asthma diagnosis.

“A hospital diagnosis of asthma or a recently filled prescription of an anti-asthmatic drug is associated with an increased risk of admission with rAAA compared with admission with intact AAA, both before and after adjusting for AAA comorbidities and relevant medications,” the researchers wrote in their analysis.

Moreover, “an asthma diagnosis or the use of bronchodilators or other anti-asthmatic drug prescriptions closer to the date of admission with AAA correlated directly with a higher risk of aortic rupture. The results remained robust after adjusting for a wide range of relevant possible confounders,” the researchers wrote.

In the cohort of patients from the vascular screening study, which included age-matched controls without AAA, asthma (measured by recent anti-asthmatic medication use) was seen associated with a significantly elevated risk of AAA before (OR = 1.45) and after adjustment for smoking (OR = 1.45) or other risk factors (OR = 1.46). This does not refer to rupture but just AAA.

Dr. Shi and colleagues noted that the AAA cohort lacked sufficient information on cigarette smoking, a known risk factor for AAA and AAA rupture, to preclude the possibility of confounding; however, the second all-male cohort did have extensive data on smoking, “and the risk of AAA among patients with asthma remained 45% higher than that of patients with nonasthma” even after adjustment.

The researchers hypothesized that an inflammatory response characterized by elevated immunoglobulin E may be the link between AAA pathogenesis and asthma, and that other allergic inflammatory diseases, including atopic dermatitis, allergic rhinitis, and some ocular allergic diseases, could potentially carry risks for AAA formation and rupture. Dr. Shi and colleagues previously investigated the IgE and aneurysm link in animal studies.

“The results have implications for the development of much needed advances in the prevention, screening criteria, and treatment of AAA, common conditions for which we currently lack sufficiently effective approaches,” the investigators wrote.

The Chinese, Danish, and U.S. governments sponsored the study. The investigators disclosed no conflicts of interest.

*CORRECTION 8/12/2020: Dr. Shi's credential was misstated in the original version on this article and has been corrected to ScD.

Patients aged 50 and older with recent active asthma are at elevated risk of abdominal aortic aneurysm and aneurysm rupture, according to new research.

A common inflammatory pathway between asthma and AAA, first observed nearly a decade ago in mice, is thought to be responsible.

The new findings, published online Feb. 11 in Arteriosclerosis, Thrombosis, and Vascular Biology (Arterioscler Thromb Vasc Biol. 2016. doi: 10.1161/ATVBAHA.115.306497) support the association in humans.

©Dr. Cong-Lin Liu

In a news release accompanying the findings, lead study author Guo-Ping Shi, ScD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, said that the findings had clear clinical implications for older patients with a recent asthma diagnosis. Such patients, particularly older men, “should be checked for signs” of abdominal aortic aneurysm, Dr. Shi said.*

For their research, Dr. Shi, along with colleagues at Zhengzhou (China) University, used data from a large Danish population-based cohort of nearly 16,000 patients (81% men) with AAA between 1996 and 2012, of which about 4,500 patients had rupture. They also looked at data from a comparison cohort of patients with and without AAA from a slightly larger population-based vascular screening trial of men in Denmark.

The investigators showed that hospital diagnosis of asthma within the previous year (n = 514) was associated with significantly higher risk of hospital admission with AAA rupture (n = 146) both before and after adjustment for AAA comorbidities (adjusted odds ratio 1.51-2.06). Higher risk of rupture also was seen for patients filling prescriptions for bronchodilators within the previous 3 months (aOR = 1.10-1.31), and for patients prescribed anti-asthma drugs (aOR OR = 1.09-1.48), which were seen as indicative of an outpatient asthma diagnosis.

“A hospital diagnosis of asthma or a recently filled prescription of an anti-asthmatic drug is associated with an increased risk of admission with rAAA compared with admission with intact AAA, both before and after adjusting for AAA comorbidities and relevant medications,” the researchers wrote in their analysis.

Moreover, “an asthma diagnosis or the use of bronchodilators or other anti-asthmatic drug prescriptions closer to the date of admission with AAA correlated directly with a higher risk of aortic rupture. The results remained robust after adjusting for a wide range of relevant possible confounders,” the researchers wrote.

In the cohort of patients from the vascular screening study, which included age-matched controls without AAA, asthma (measured by recent anti-asthmatic medication use) was seen associated with a significantly elevated risk of AAA before (OR = 1.45) and after adjustment for smoking (OR = 1.45) or other risk factors (OR = 1.46). This does not refer to rupture but just AAA.

Dr. Shi and colleagues noted that the AAA cohort lacked sufficient information on cigarette smoking, a known risk factor for AAA and AAA rupture, to preclude the possibility of confounding; however, the second all-male cohort did have extensive data on smoking, “and the risk of AAA among patients with asthma remained 45% higher than that of patients with nonasthma” even after adjustment.

The researchers hypothesized that an inflammatory response characterized by elevated immunoglobulin E may be the link between AAA pathogenesis and asthma, and that other allergic inflammatory diseases, including atopic dermatitis, allergic rhinitis, and some ocular allergic diseases, could potentially carry risks for AAA formation and rupture. Dr. Shi and colleagues previously investigated the IgE and aneurysm link in animal studies.

“The results have implications for the development of much needed advances in the prevention, screening criteria, and treatment of AAA, common conditions for which we currently lack sufficiently effective approaches,” the investigators wrote.

The Chinese, Danish, and U.S. governments sponsored the study. The investigators disclosed no conflicts of interest.

*CORRECTION 8/12/2020: Dr. Shi's credential was misstated in the original version on this article and has been corrected to ScD.

What does your patient need to know at the first visit? Why is this information important?

At the first visit I discuss potential side effects. The ones that patients want to hear about are infection and cancer. Clinical studies do not seem to indicate an increased risk for infection. But is that what I tell the patient? No. I tell the patient that there may be a slightly increased risk for infection with biologics. I tell patients the prescribing information lists some rare and serious infections such as tuberculosis, hepatitis B reactivation, sepsis, invasive fungal infections, and opportunistic infections. I do say that if the patient is young and healthy, the risk is relatively low. I do tell the patient that we do check the things that we can check, such as screening for tuberculosis and hepatitis B virus.

Once a patient starts a biologic, I ask him/her to tell me or the primary care physician if he/she develops fevers, chills, weight loss, chronic cough, or an illness that lasts 1 week or more. I emphasize that high-risk patients—those who are elderly, have chronic kidney or liver disease, or have uncontrolled diabetes—should be more vigilant for signs of infection than otherwise-healthy patients.

The word cancer is scary for patients, so I mention that patients with psoriasis are more likely to develop lymphoma, which may be related to having psoriasis itself, not to therapies used to treat psoriasis. For tumor necrosis factor inhibitors, there is a warning about an increased risk for nonmelanoma skin cancers, which has been confirmed in some studies, so I tell patients that it is important to come in at least every 6 months to evaluate their psoriasis but also to check for skin cancers.

I also review with patients that many times their insurance company will require them to fail a traditional systemic therapy first before they can start a biologic. Also, monthly co-pays for a biologic likely will be higher than oral therapies they have used.

How do you keep patients compliant with treatment?

Patients usually want to be compliant on their own, as they will see how effective the biologic is and how clear their skin will become while on therapy. They will see that if they take a break for whatever reason (eg, ran out of medicine, went on vacation, loss of medical insurance), the psoriasis will return, perhaps with a vengeance.

I remind patients who are not compliant with biologic therapy that the body may produce antibodies against the biologic itself if there is a substantial break from therapy, which may make the biologic less effective over time.

If the patient wants to reduce the dose but not stop it completely, I recommend to increase the interval of the maintenance dosing by 1 day after each injection and see if the psoriasis slowly returns. If it does return, then he/she should reduce the interval of the maintenance dosing by 1 day and hold that interval.

What do you do if they refuse treatment?

I stress to patients that biologics are typically the best long-term treatment with the highest levels of effectiveness and safety for psoriasis. In the rare case of a patient refusing a biologic, I discuss other options such as oral therapy (eg, methotrexate, cyclosporine, acitretin, apremilast) or phototherapy. If the patient is a candidate for biologic therapy, topical therapy may not be adequate to treat a large body surface area affected.

What resources do you recommend to patients for more information?

The National Psoriasis Foundation has recently published an updated patient booklet, “Systemic Medications for Psoriasis and Psoriatic Arthritis,” that I would encourage all patients to read for further information.

Suggested Reading

National Psoriasis Foundation. Systemic medications for psoriasis and psoriatic arthritis. https://www.psoriasis.org/sites/default/files/systemics_booklet.pdf. Accessed January 11, 2016.

What does your patient need to know at the first visit? Why is this information important?

At the first visit I discuss potential side effects. The ones that patients want to hear about are infection and cancer. Clinical studies do not seem to indicate an increased risk for infection. But is that what I tell the patient? No. I tell the patient that there may be a slightly increased risk for infection with biologics. I tell patients the prescribing information lists some rare and serious infections such as tuberculosis, hepatitis B reactivation, sepsis, invasive fungal infections, and opportunistic infections. I do say that if the patient is young and healthy, the risk is relatively low. I do tell the patient that we do check the things that we can check, such as screening for tuberculosis and hepatitis B virus.

Once a patient starts a biologic, I ask him/her to tell me or the primary care physician if he/she develops fevers, chills, weight loss, chronic cough, or an illness that lasts 1 week or more. I emphasize that high-risk patients—those who are elderly, have chronic kidney or liver disease, or have uncontrolled diabetes—should be more vigilant for signs of infection than otherwise-healthy patients.

The word cancer is scary for patients, so I mention that patients with psoriasis are more likely to develop lymphoma, which may be related to having psoriasis itself, not to therapies used to treat psoriasis. For tumor necrosis factor inhibitors, there is a warning about an increased risk for nonmelanoma skin cancers, which has been confirmed in some studies, so I tell patients that it is important to come in at least every 6 months to evaluate their psoriasis but also to check for skin cancers.

I also review with patients that many times their insurance company will require them to fail a traditional systemic therapy first before they can start a biologic. Also, monthly co-pays for a biologic likely will be higher than oral therapies they have used.

How do you keep patients compliant with treatment?

Patients usually want to be compliant on their own, as they will see how effective the biologic is and how clear their skin will become while on therapy. They will see that if they take a break for whatever reason (eg, ran out of medicine, went on vacation, loss of medical insurance), the psoriasis will return, perhaps with a vengeance.

I remind patients who are not compliant with biologic therapy that the body may produce antibodies against the biologic itself if there is a substantial break from therapy, which may make the biologic less effective over time.

If the patient wants to reduce the dose but not stop it completely, I recommend to increase the interval of the maintenance dosing by 1 day after each injection and see if the psoriasis slowly returns. If it does return, then he/she should reduce the interval of the maintenance dosing by 1 day and hold that interval.

What do you do if they refuse treatment?

I stress to patients that biologics are typically the best long-term treatment with the highest levels of effectiveness and safety for psoriasis. In the rare case of a patient refusing a biologic, I discuss other options such as oral therapy (eg, methotrexate, cyclosporine, acitretin, apremilast) or phototherapy. If the patient is a candidate for biologic therapy, topical therapy may not be adequate to treat a large body surface area affected.

What resources do you recommend to patients for more information?

The National Psoriasis Foundation has recently published an updated patient booklet, “Systemic Medications for Psoriasis and Psoriatic Arthritis,” that I would encourage all patients to read for further information.

Suggested Reading

National Psoriasis Foundation. Systemic medications for psoriasis and psoriatic arthritis. https://www.psoriasis.org/sites/default/files/systemics_booklet.pdf. Accessed January 11, 2016.

What does your patient need to know at the first visit? Why is this information important?

At the first visit I discuss potential side effects. The ones that patients want to hear about are infection and cancer. Clinical studies do not seem to indicate an increased risk for infection. But is that what I tell the patient? No. I tell the patient that there may be a slightly increased risk for infection with biologics. I tell patients the prescribing information lists some rare and serious infections such as tuberculosis, hepatitis B reactivation, sepsis, invasive fungal infections, and opportunistic infections. I do say that if the patient is young and healthy, the risk is relatively low. I do tell the patient that we do check the things that we can check, such as screening for tuberculosis and hepatitis B virus.

Once a patient starts a biologic, I ask him/her to tell me or the primary care physician if he/she develops fevers, chills, weight loss, chronic cough, or an illness that lasts 1 week or more. I emphasize that high-risk patients—those who are elderly, have chronic kidney or liver disease, or have uncontrolled diabetes—should be more vigilant for signs of infection than otherwise-healthy patients.

The word cancer is scary for patients, so I mention that patients with psoriasis are more likely to develop lymphoma, which may be related to having psoriasis itself, not to therapies used to treat psoriasis. For tumor necrosis factor inhibitors, there is a warning about an increased risk for nonmelanoma skin cancers, which has been confirmed in some studies, so I tell patients that it is important to come in at least every 6 months to evaluate their psoriasis but also to check for skin cancers.

I also review with patients that many times their insurance company will require them to fail a traditional systemic therapy first before they can start a biologic. Also, monthly co-pays for a biologic likely will be higher than oral therapies they have used.

How do you keep patients compliant with treatment?

Patients usually want to be compliant on their own, as they will see how effective the biologic is and how clear their skin will become while on therapy. They will see that if they take a break for whatever reason (eg, ran out of medicine, went on vacation, loss of medical insurance), the psoriasis will return, perhaps with a vengeance.

I remind patients who are not compliant with biologic therapy that the body may produce antibodies against the biologic itself if there is a substantial break from therapy, which may make the biologic less effective over time.

If the patient wants to reduce the dose but not stop it completely, I recommend to increase the interval of the maintenance dosing by 1 day after each injection and see if the psoriasis slowly returns. If it does return, then he/she should reduce the interval of the maintenance dosing by 1 day and hold that interval.

What do you do if they refuse treatment?

I stress to patients that biologics are typically the best long-term treatment with the highest levels of effectiveness and safety for psoriasis. In the rare case of a patient refusing a biologic, I discuss other options such as oral therapy (eg, methotrexate, cyclosporine, acitretin, apremilast) or phototherapy. If the patient is a candidate for biologic therapy, topical therapy may not be adequate to treat a large body surface area affected.

What resources do you recommend to patients for more information?

The National Psoriasis Foundation has recently published an updated patient booklet, “Systemic Medications for Psoriasis and Psoriatic Arthritis,” that I would encourage all patients to read for further information.

Suggested Reading

National Psoriasis Foundation. Systemic medications for psoriasis and psoriatic arthritis. https://www.psoriasis.org/sites/default/files/systemics_booklet.pdf. Accessed January 11, 2016.

SNOWMASS, COLO. – The primary treatment goal in patients hospitalized for acute decompensated heart failure is aggressive decongestion to get them feeling better and out of the hospital quicker – and the best way to achieve that is with high-dose loop diuretics administered intravenously at a dose equivalent to 2.5 times the previous oral dose, Dr. Akshay S. Desai said at the Annual Cardiovascular Conference at Snowmass.

This was the key lesson of the Diuretic Optimization Strategies Evaluation (DOSE) trial, a prospective double-blind randomized trial that provides physicians with the best available data on how to decongest patients with acute decompensated heart failure (ADHF), according to Dr. Desai, a coinvestigator. The study was conducted by the National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network.

The DOSE trial showed that it really doesn’t matter whether the diuretic is administered intravenously by continuous infusion or a bolus every 12 hours. The important thing is the high-dose strategy. It proved to be safe and was associated with accelerated decongestion as manifest in greater relief of dyspnea, greater weight loss and fluid loss, and a larger reduction in serum brain natriuretic peptide at 72 hours than low-dose therapy equivalent to the patient’s previous oral dose (N Engl J Med. 2011 Mar 3;364[9]:797-805).

“The message for you in practice is that the route of diuretic administration is probably not important as long as you give an adequate dose. I would consider giving the higher dose of diuretic because it’s associated with more effective decongestion and perhaps shorter length of stay,” said Dr. Desai, director of heart failure disease management at Brigham and Women’s Hospital in Boston.

There is a trade-off in ADHF between effective decongestion and worsening renal function as reflected in increased serum creatinine levels. Transient worsening of renal function occurred more frequently with the high-dose strategy in the DOSE trial, but it had no impact on clinical outcomes at 60 days follow-up. This finding is consistent with the results of an important Italian study showing that worsening renal function alone isn’t independently associated with increased risk of death or ADHF readmission; the problems arise in patients with worsening renal function and persistent congestion (Circ Heart Fail. 2012 Jan;5[1]:54-62).

Worsening congestion drives most hospitalizations for heart failure. And patients who are still congested at discharge are at dramatically increased risk for death or readmission in the ensuing 6 months. Yet the limitations of current therapy mean that even in expert hands, a substantial proportion of patients are discharged with clinically significant congestion. For example, in a retrospective analysis of nearly 500 patients enrolled in ADHF studies conducted by physicians in the NHLBI Heart Failure Clinical Research Network, only 52% were discharged free of congestion (Circ Heart Fail. 2015 Jul;8[4]:741-8).

Beyond aggressive treatment with loop diuretics, what else is useful in achieving the goal of hospital discharge with normalized filling pressures? Not much, according to a considerable body of research on the topic.

“The data tell us more about what not to do than what to do,” according to Dr. Desai.

For example, even though aggressive salt and fluid restriction is often forced upon patients hospitalized for ADHF on the rationale that this strategy may make it easier for diuretics to work, it’s not an evidence-based practice. Indeed, in a randomized clinical trial with blinded outcome assessments, an in-hospital diet restricted to a maximum intake of 800 mg of sodium and 800 mL of fluid daily had no effect on weight loss or a clinical congestion score (JAMA Intern Med. 2013 June 24;173[12]:1058-64).

“What it did very effectively was make patients thirsty. There are probably some patients where restriction of sodium and fluid intake is important, but routine use of tight restrictions is probably more harmful than helpful,” he observed.

The list of failed once-promising alternatives to diuretics in the setting of ADHF is impressive. It includes milrinone, tolvaptan, nesiritide, levosimendan, tezosentan, low-dose dopamine, and ultrafiltration. All had a sound mechanistic basis for the belief that they might improve outcomes, but in clinical trials none of them did.

Although routine use of pulmonary artery catheters to guide decongestion therapy in ADHF isn’t warranted because it has not been shown to be better than clinical assessment, there are certain situations where it is extremely helpful. For example, in the patient who isn’t responding to adequate doses of loop diuretics, it becomes important to understand the hemodynamics, which may involve systemic vascular resistance or a cardiac output problem.

Other situations where it’s worthwhile to consider placement of a pulmonary artery catheter include the patient of uncertain fluid status where it’s not possible to confidently estimate cardiac output at the bedside or markedly worsening renal function with empiric therapy.

Dr. Desai reported receiving research funding from Novartis and St. Jude Medical and serving as a paid consultant to Merck, Relypsa, and St. Jude Medical.

[email protected]

SNOWMASS, COLO. – The primary treatment goal in patients hospitalized for acute decompensated heart failure is aggressive decongestion to get them feeling better and out of the hospital quicker – and the best way to achieve that is with high-dose loop diuretics administered intravenously at a dose equivalent to 2.5 times the previous oral dose, Dr. Akshay S. Desai said at the Annual Cardiovascular Conference at Snowmass.

This was the key lesson of the Diuretic Optimization Strategies Evaluation (DOSE) trial, a prospective double-blind randomized trial that provides physicians with the best available data on how to decongest patients with acute decompensated heart failure (ADHF), according to Dr. Desai, a coinvestigator. The study was conducted by the National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network.

The DOSE trial showed that it really doesn’t matter whether the diuretic is administered intravenously by continuous infusion or a bolus every 12 hours. The important thing is the high-dose strategy. It proved to be safe and was associated with accelerated decongestion as manifest in greater relief of dyspnea, greater weight loss and fluid loss, and a larger reduction in serum brain natriuretic peptide at 72 hours than low-dose therapy equivalent to the patient’s previous oral dose (N Engl J Med. 2011 Mar 3;364[9]:797-805).

“The message for you in practice is that the route of diuretic administration is probably not important as long as you give an adequate dose. I would consider giving the higher dose of diuretic because it’s associated with more effective decongestion and perhaps shorter length of stay,” said Dr. Desai, director of heart failure disease management at Brigham and Women’s Hospital in Boston.

There is a trade-off in ADHF between effective decongestion and worsening renal function as reflected in increased serum creatinine levels. Transient worsening of renal function occurred more frequently with the high-dose strategy in the DOSE trial, but it had no impact on clinical outcomes at 60 days follow-up. This finding is consistent with the results of an important Italian study showing that worsening renal function alone isn’t independently associated with increased risk of death or ADHF readmission; the problems arise in patients with worsening renal function and persistent congestion (Circ Heart Fail. 2012 Jan;5[1]:54-62).

Worsening congestion drives most hospitalizations for heart failure. And patients who are still congested at discharge are at dramatically increased risk for death or readmission in the ensuing 6 months. Yet the limitations of current therapy mean that even in expert hands, a substantial proportion of patients are discharged with clinically significant congestion. For example, in a retrospective analysis of nearly 500 patients enrolled in ADHF studies conducted by physicians in the NHLBI Heart Failure Clinical Research Network, only 52% were discharged free of congestion (Circ Heart Fail. 2015 Jul;8[4]:741-8).

Beyond aggressive treatment with loop diuretics, what else is useful in achieving the goal of hospital discharge with normalized filling pressures? Not much, according to a considerable body of research on the topic.

“The data tell us more about what not to do than what to do,” according to Dr. Desai.

For example, even though aggressive salt and fluid restriction is often forced upon patients hospitalized for ADHF on the rationale that this strategy may make it easier for diuretics to work, it’s not an evidence-based practice. Indeed, in a randomized clinical trial with blinded outcome assessments, an in-hospital diet restricted to a maximum intake of 800 mg of sodium and 800 mL of fluid daily had no effect on weight loss or a clinical congestion score (JAMA Intern Med. 2013 June 24;173[12]:1058-64).

“What it did very effectively was make patients thirsty. There are probably some patients where restriction of sodium and fluid intake is important, but routine use of tight restrictions is probably more harmful than helpful,” he observed.

The list of failed once-promising alternatives to diuretics in the setting of ADHF is impressive. It includes milrinone, tolvaptan, nesiritide, levosimendan, tezosentan, low-dose dopamine, and ultrafiltration. All had a sound mechanistic basis for the belief that they might improve outcomes, but in clinical trials none of them did.

Although routine use of pulmonary artery catheters to guide decongestion therapy in ADHF isn’t warranted because it has not been shown to be better than clinical assessment, there are certain situations where it is extremely helpful. For example, in the patient who isn’t responding to adequate doses of loop diuretics, it becomes important to understand the hemodynamics, which may involve systemic vascular resistance or a cardiac output problem.

Other situations where it’s worthwhile to consider placement of a pulmonary artery catheter include the patient of uncertain fluid status where it’s not possible to confidently estimate cardiac output at the bedside or markedly worsening renal function with empiric therapy.

Dr. Desai reported receiving research funding from Novartis and St. Jude Medical and serving as a paid consultant to Merck, Relypsa, and St. Jude Medical.

[email protected]

SNOWMASS, COLO. – The primary treatment goal in patients hospitalized for acute decompensated heart failure is aggressive decongestion to get them feeling better and out of the hospital quicker – and the best way to achieve that is with high-dose loop diuretics administered intravenously at a dose equivalent to 2.5 times the previous oral dose, Dr. Akshay S. Desai said at the Annual Cardiovascular Conference at Snowmass.

This was the key lesson of the Diuretic Optimization Strategies Evaluation (DOSE) trial, a prospective double-blind randomized trial that provides physicians with the best available data on how to decongest patients with acute decompensated heart failure (ADHF), according to Dr. Desai, a coinvestigator. The study was conducted by the National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network.

The DOSE trial showed that it really doesn’t matter whether the diuretic is administered intravenously by continuous infusion or a bolus every 12 hours. The important thing is the high-dose strategy. It proved to be safe and was associated with accelerated decongestion as manifest in greater relief of dyspnea, greater weight loss and fluid loss, and a larger reduction in serum brain natriuretic peptide at 72 hours than low-dose therapy equivalent to the patient’s previous oral dose (N Engl J Med. 2011 Mar 3;364[9]:797-805).

“The message for you in practice is that the route of diuretic administration is probably not important as long as you give an adequate dose. I would consider giving the higher dose of diuretic because it’s associated with more effective decongestion and perhaps shorter length of stay,” said Dr. Desai, director of heart failure disease management at Brigham and Women’s Hospital in Boston.

There is a trade-off in ADHF between effective decongestion and worsening renal function as reflected in increased serum creatinine levels. Transient worsening of renal function occurred more frequently with the high-dose strategy in the DOSE trial, but it had no impact on clinical outcomes at 60 days follow-up. This finding is consistent with the results of an important Italian study showing that worsening renal function alone isn’t independently associated with increased risk of death or ADHF readmission; the problems arise in patients with worsening renal function and persistent congestion (Circ Heart Fail. 2012 Jan;5[1]:54-62).

Worsening congestion drives most hospitalizations for heart failure. And patients who are still congested at discharge are at dramatically increased risk for death or readmission in the ensuing 6 months. Yet the limitations of current therapy mean that even in expert hands, a substantial proportion of patients are discharged with clinically significant congestion. For example, in a retrospective analysis of nearly 500 patients enrolled in ADHF studies conducted by physicians in the NHLBI Heart Failure Clinical Research Network, only 52% were discharged free of congestion (Circ Heart Fail. 2015 Jul;8[4]:741-8).

Beyond aggressive treatment with loop diuretics, what else is useful in achieving the goal of hospital discharge with normalized filling pressures? Not much, according to a considerable body of research on the topic.

“The data tell us more about what not to do than what to do,” according to Dr. Desai.

For example, even though aggressive salt and fluid restriction is often forced upon patients hospitalized for ADHF on the rationale that this strategy may make it easier for diuretics to work, it’s not an evidence-based practice. Indeed, in a randomized clinical trial with blinded outcome assessments, an in-hospital diet restricted to a maximum intake of 800 mg of sodium and 800 mL of fluid daily had no effect on weight loss or a clinical congestion score (JAMA Intern Med. 2013 June 24;173[12]:1058-64).

“What it did very effectively was make patients thirsty. There are probably some patients where restriction of sodium and fluid intake is important, but routine use of tight restrictions is probably more harmful than helpful,” he observed.

The list of failed once-promising alternatives to diuretics in the setting of ADHF is impressive. It includes milrinone, tolvaptan, nesiritide, levosimendan, tezosentan, low-dose dopamine, and ultrafiltration. All had a sound mechanistic basis for the belief that they might improve outcomes, but in clinical trials none of them did.

Although routine use of pulmonary artery catheters to guide decongestion therapy in ADHF isn’t warranted because it has not been shown to be better than clinical assessment, there are certain situations where it is extremely helpful. For example, in the patient who isn’t responding to adequate doses of loop diuretics, it becomes important to understand the hemodynamics, which may involve systemic vascular resistance or a cardiac output problem.

Other situations where it’s worthwhile to consider placement of a pulmonary artery catheter include the patient of uncertain fluid status where it’s not possible to confidently estimate cardiac output at the bedside or markedly worsening renal function with empiric therapy.

Dr. Desai reported receiving research funding from Novartis and St. Jude Medical and serving as a paid consultant to Merck, Relypsa, and St. Jude Medical.

[email protected]

The U.S. program to develop biosimilar agents – somewhat akin to generic drugs for complex, biologic molecules that have come off patent protection – is gathering momentum, with the first U.S. biosimilar, Zarxio, approved by the Food and Drug Administration in March 2015 and with the second, a biosimilar to infliximab, recommended by an FDA advisory committee on Feb. 9 of this year.

What’s striking about the burgeoning biosimilar development process, created by the Affordable Care Act, is how it has morphed the FDA from its traditional role as an objective arbiter of a drug’s safety and efficacy into an active partner in shepherding biosimilars onto the market.

As explained on Feb. 4 in testimony before a Congressional committee by Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, the Biologic Price Competition and Innovation Act that was part of the Affordable Care Act launched a new U.S. drug-development pathway expressly for biosimilars. To implement that law, the FDA created an entirely new infrastructure within the agency – the Biosimilar Product Development Program – to help guide prospective manufacturers (called sponsors) of biosimilars through the regulatory and research hurdles to get a new biosimilar approved and into the hands of U.S. patients.

According to Dr. Woodcock, this program involves many steps where FDA staffers provide “review” and “advice” to sponsors on the studies they need to conduct and the analysis they need to perform to get their new products to market. The sponsor joins this program by paying an upfront fee that the FDA uses to keep the program running. Once a sponsor of a prospective biosimilar is in the program, the FDA’s staff helps guide the biosimilar development to a smooth conclusion.

To some extent, the FDA staff fills a similar role for conventional drug-development enterprises, conferring with manufacturers from the outset on matters such as the types and design of studies needed to insure success. What’s different about the biosimilar program is that conventional-drug development went on well before the FDA (or its predecessor) entered the scene, and the U.S. government created the FDA to police and regulate the drug production industry and protect the public against unscrupulous manufacturers of ineffective or dangerous drugs.

In contrast, the FDA itself created this new biosimilar development structure, and Dr. Woodcock noted that the in-depth review and advice meetings that the FDA offers to prospective biosimilar sponsors “has no counterpart in the Prescription Drug User Fee Act program and is unique” to the biosimilar program.

The consequence of having the FDA create the biosimilar development program from the ground up and structure it to provide such intimate input from the agency to sponsors at every step of the way seems to give the agency a notable and somewhat unnerving investment in the program’s success.

Dr. Woodcock called the approval of Zarxio an “exciting accomplishment,” and in her testimony before Congress she trumpeted the fact that as of January 2016 the biosimilar program was working on 59 proposed products that would mimic 18 different reference-product biologics. She also said that the FDA is “excited about the growing demand” for biosimilar-oriented meetings and marketing applications.

Don’t get me wrong: I think that the biosimilar concept is great, and has the potential to make what have become life-changing treatments more affordable and more available. And making the FDA such an active participant in getting biosimilar drugs created and approved is undoubtedly the most efficient way to accomplish this.

But in the process, the biosimilar program has changed the FDA from its more disengaged role as objective pharmaceutical judge into an active and seemingly not completely neutral codeveloper, risking at least the appearance of lost impartiality. Given that the FDA now wears two very different hats, we need to trust that the integrity and dedication of its staff will keep them from confusing their roles as proponent and gatekeeper.

[email protected]

On Twitter @mitchelzoler

The U.S. program to develop biosimilar agents – somewhat akin to generic drugs for complex, biologic molecules that have come off patent protection – is gathering momentum, with the first U.S. biosimilar, Zarxio, approved by the Food and Drug Administration in March 2015 and with the second, a biosimilar to infliximab, recommended by an FDA advisory committee on Feb. 9 of this year.

What’s striking about the burgeoning biosimilar development process, created by the Affordable Care Act, is how it has morphed the FDA from its traditional role as an objective arbiter of a drug’s safety and efficacy into an active partner in shepherding biosimilars onto the market.

As explained on Feb. 4 in testimony before a Congressional committee by Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, the Biologic Price Competition and Innovation Act that was part of the Affordable Care Act launched a new U.S. drug-development pathway expressly for biosimilars. To implement that law, the FDA created an entirely new infrastructure within the agency – the Biosimilar Product Development Program – to help guide prospective manufacturers (called sponsors) of biosimilars through the regulatory and research hurdles to get a new biosimilar approved and into the hands of U.S. patients.

According to Dr. Woodcock, this program involves many steps where FDA staffers provide “review” and “advice” to sponsors on the studies they need to conduct and the analysis they need to perform to get their new products to market. The sponsor joins this program by paying an upfront fee that the FDA uses to keep the program running. Once a sponsor of a prospective biosimilar is in the program, the FDA’s staff helps guide the biosimilar development to a smooth conclusion.

To some extent, the FDA staff fills a similar role for conventional drug-development enterprises, conferring with manufacturers from the outset on matters such as the types and design of studies needed to insure success. What’s different about the biosimilar program is that conventional-drug development went on well before the FDA (or its predecessor) entered the scene, and the U.S. government created the FDA to police and regulate the drug production industry and protect the public against unscrupulous manufacturers of ineffective or dangerous drugs.

In contrast, the FDA itself created this new biosimilar development structure, and Dr. Woodcock noted that the in-depth review and advice meetings that the FDA offers to prospective biosimilar sponsors “has no counterpart in the Prescription Drug User Fee Act program and is unique” to the biosimilar program.

The consequence of having the FDA create the biosimilar development program from the ground up and structure it to provide such intimate input from the agency to sponsors at every step of the way seems to give the agency a notable and somewhat unnerving investment in the program’s success.

Dr. Woodcock called the approval of Zarxio an “exciting accomplishment,” and in her testimony before Congress she trumpeted the fact that as of January 2016 the biosimilar program was working on 59 proposed products that would mimic 18 different reference-product biologics. She also said that the FDA is “excited about the growing demand” for biosimilar-oriented meetings and marketing applications.

Don’t get me wrong: I think that the biosimilar concept is great, and has the potential to make what have become life-changing treatments more affordable and more available. And making the FDA such an active participant in getting biosimilar drugs created and approved is undoubtedly the most efficient way to accomplish this.

But in the process, the biosimilar program has changed the FDA from its more disengaged role as objective pharmaceutical judge into an active and seemingly not completely neutral codeveloper, risking at least the appearance of lost impartiality. Given that the FDA now wears two very different hats, we need to trust that the integrity and dedication of its staff will keep them from confusing their roles as proponent and gatekeeper.

[email protected]

On Twitter @mitchelzoler

The U.S. program to develop biosimilar agents – somewhat akin to generic drugs for complex, biologic molecules that have come off patent protection – is gathering momentum, with the first U.S. biosimilar, Zarxio, approved by the Food and Drug Administration in March 2015 and with the second, a biosimilar to infliximab, recommended by an FDA advisory committee on Feb. 9 of this year.

What’s striking about the burgeoning biosimilar development process, created by the Affordable Care Act, is how it has morphed the FDA from its traditional role as an objective arbiter of a drug’s safety and efficacy into an active partner in shepherding biosimilars onto the market.

As explained on Feb. 4 in testimony before a Congressional committee by Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, the Biologic Price Competition and Innovation Act that was part of the Affordable Care Act launched a new U.S. drug-development pathway expressly for biosimilars. To implement that law, the FDA created an entirely new infrastructure within the agency – the Biosimilar Product Development Program – to help guide prospective manufacturers (called sponsors) of biosimilars through the regulatory and research hurdles to get a new biosimilar approved and into the hands of U.S. patients.

According to Dr. Woodcock, this program involves many steps where FDA staffers provide “review” and “advice” to sponsors on the studies they need to conduct and the analysis they need to perform to get their new products to market. The sponsor joins this program by paying an upfront fee that the FDA uses to keep the program running. Once a sponsor of a prospective biosimilar is in the program, the FDA’s staff helps guide the biosimilar development to a smooth conclusion.

To some extent, the FDA staff fills a similar role for conventional drug-development enterprises, conferring with manufacturers from the outset on matters such as the types and design of studies needed to insure success. What’s different about the biosimilar program is that conventional-drug development went on well before the FDA (or its predecessor) entered the scene, and the U.S. government created the FDA to police and regulate the drug production industry and protect the public against unscrupulous manufacturers of ineffective or dangerous drugs.

In contrast, the FDA itself created this new biosimilar development structure, and Dr. Woodcock noted that the in-depth review and advice meetings that the FDA offers to prospective biosimilar sponsors “has no counterpart in the Prescription Drug User Fee Act program and is unique” to the biosimilar program.

The consequence of having the FDA create the biosimilar development program from the ground up and structure it to provide such intimate input from the agency to sponsors at every step of the way seems to give the agency a notable and somewhat unnerving investment in the program’s success.

Dr. Woodcock called the approval of Zarxio an “exciting accomplishment,” and in her testimony before Congress she trumpeted the fact that as of January 2016 the biosimilar program was working on 59 proposed products that would mimic 18 different reference-product biologics. She also said that the FDA is “excited about the growing demand” for biosimilar-oriented meetings and marketing applications.

Don’t get me wrong: I think that the biosimilar concept is great, and has the potential to make what have become life-changing treatments more affordable and more available. And making the FDA such an active participant in getting biosimilar drugs created and approved is undoubtedly the most efficient way to accomplish this.

But in the process, the biosimilar program has changed the FDA from its more disengaged role as objective pharmaceutical judge into an active and seemingly not completely neutral codeveloper, risking at least the appearance of lost impartiality. Given that the FDA now wears two very different hats, we need to trust that the integrity and dedication of its staff will keep them from confusing their roles as proponent and gatekeeper.

[email protected]

On Twitter @mitchelzoler

The significantly increased risk of myocardial infarction or stroke in patients with bipolar I disorder appears to be tied more to preventive factors than to cardiovascular risk factors. However, bipolar I patients with a history of psychosis have an marginally increased risk of MI or stroke, a population-based cohort study showed.

The researchers came to those conclusions after analyzing residents’ health records and death certificates in Olmsted County, Minn., which were contained within the Rochester Epidemiology Project database. The study’s participants included 334 patients with bipolar I disorder and 334 people without bipolar disorder, although one of the patients who did not have bipolar I at the beginning of the study was later diagnosed with the disorder. All participants had been residents of Olmsted County from Jan. 1, 1966, through Dec. 31,1996.

Patients continued to be followed until Dec. 31, 2013, unless one of the following events occurred before that date: the patient had an MI or stroke, was lost to follow-up, or died before the end of the study. A patient experiencing an MI, stroke, or death or a patient disappearing from the database triggered an end to that patient’s participation in the study.

When an individual having an MI or a stroke was treated as a composite outcome, bipolar I disorder patients had a significantly increased risk of experiencing a fatal or non-fatal MI or stroke, compared with the individuals in the control group (P = .04). The risk was no longer significant after the researchers adjusted for the following potential baseline confounders of the association between bipolar disorder and cardiovascular disease: alcohol use disorder, diabetes, hypertension, and smoking (P = .46).

Meanwhile, a secondary analysis of the data showed that history of psychosis was indeed tied to a marginally increased risk of MI or stroke (P =.06).

“It will be fundamental to improve current preventive strategies to decrease the prevalence of smoking, alcohol use, hypertension, and diabetes among patients with bipolar disorder,” said Dr. Miguel L. Prieto of the department of psychiatry and psychology at the Mayo Medical School, Rochester, Minn., and his colleagues. “Moreover, we detected a possible higher risk of MI/stroke in the subgroup of patients with history of psychosis that certainly warrants replication.”

Future research also should seek to determine early biomarkers of atherosclerosis, the researchers said.

Read the study in Journal of Affective Disorders (doi: 10.1016/j.jad.2016.01.015).

[email protected]

The significantly increased risk of myocardial infarction or stroke in patients with bipolar I disorder appears to be tied more to preventive factors than to cardiovascular risk factors. However, bipolar I patients with a history of psychosis have an marginally increased risk of MI or stroke, a population-based cohort study showed.

The researchers came to those conclusions after analyzing residents’ health records and death certificates in Olmsted County, Minn., which were contained within the Rochester Epidemiology Project database. The study’s participants included 334 patients with bipolar I disorder and 334 people without bipolar disorder, although one of the patients who did not have bipolar I at the beginning of the study was later diagnosed with the disorder. All participants had been residents of Olmsted County from Jan. 1, 1966, through Dec. 31,1996.

Patients continued to be followed until Dec. 31, 2013, unless one of the following events occurred before that date: the patient had an MI or stroke, was lost to follow-up, or died before the end of the study. A patient experiencing an MI, stroke, or death or a patient disappearing from the database triggered an end to that patient’s participation in the study.

When an individual having an MI or a stroke was treated as a composite outcome, bipolar I disorder patients had a significantly increased risk of experiencing a fatal or non-fatal MI or stroke, compared with the individuals in the control group (P = .04). The risk was no longer significant after the researchers adjusted for the following potential baseline confounders of the association between bipolar disorder and cardiovascular disease: alcohol use disorder, diabetes, hypertension, and smoking (P = .46).

Meanwhile, a secondary analysis of the data showed that history of psychosis was indeed tied to a marginally increased risk of MI or stroke (P =.06).

“It will be fundamental to improve current preventive strategies to decrease the prevalence of smoking, alcohol use, hypertension, and diabetes among patients with bipolar disorder,” said Dr. Miguel L. Prieto of the department of psychiatry and psychology at the Mayo Medical School, Rochester, Minn., and his colleagues. “Moreover, we detected a possible higher risk of MI/stroke in the subgroup of patients with history of psychosis that certainly warrants replication.”

Future research also should seek to determine early biomarkers of atherosclerosis, the researchers said.

Read the study in Journal of Affective Disorders (doi: 10.1016/j.jad.2016.01.015).

[email protected]

The significantly increased risk of myocardial infarction or stroke in patients with bipolar I disorder appears to be tied more to preventive factors than to cardiovascular risk factors. However, bipolar I patients with a history of psychosis have an marginally increased risk of MI or stroke, a population-based cohort study showed.

The researchers came to those conclusions after analyzing residents’ health records and death certificates in Olmsted County, Minn., which were contained within the Rochester Epidemiology Project database. The study’s participants included 334 patients with bipolar I disorder and 334 people without bipolar disorder, although one of the patients who did not have bipolar I at the beginning of the study was later diagnosed with the disorder. All participants had been residents of Olmsted County from Jan. 1, 1966, through Dec. 31,1996.

Patients continued to be followed until Dec. 31, 2013, unless one of the following events occurred before that date: the patient had an MI or stroke, was lost to follow-up, or died before the end of the study. A patient experiencing an MI, stroke, or death or a patient disappearing from the database triggered an end to that patient’s participation in the study.

When an individual having an MI or a stroke was treated as a composite outcome, bipolar I disorder patients had a significantly increased risk of experiencing a fatal or non-fatal MI or stroke, compared with the individuals in the control group (P = .04). The risk was no longer significant after the researchers adjusted for the following potential baseline confounders of the association between bipolar disorder and cardiovascular disease: alcohol use disorder, diabetes, hypertension, and smoking (P = .46).

Meanwhile, a secondary analysis of the data showed that history of psychosis was indeed tied to a marginally increased risk of MI or stroke (P =.06).

“It will be fundamental to improve current preventive strategies to decrease the prevalence of smoking, alcohol use, hypertension, and diabetes among patients with bipolar disorder,” said Dr. Miguel L. Prieto of the department of psychiatry and psychology at the Mayo Medical School, Rochester, Minn., and his colleagues. “Moreover, we detected a possible higher risk of MI/stroke in the subgroup of patients with history of psychosis that certainly warrants replication.”

Future research also should seek to determine early biomarkers of atherosclerosis, the researchers said.

Read the study in Journal of Affective Disorders (doi: 10.1016/j.jad.2016.01.015).

[email protected]

SNOWMASS, COLO. – The goal is finally in sight following an odyssey to develop the Watchman left atrial appendage closure device as a safe and effective alternative to oral anticoagulation for stroke prevention in patients with nonvalvular atrial fibrillation, Dr. David R. Holmes Jr. said at the Annual Cardiovascular Conference at Snowmass.

It’s all coming together: The Watchman, a small percutaneously delivered parachute-like device, has received FDA marketing approval as the sole authorized left atrial appendage closure device in this country on the strength of two compellingly positive randomized controlled trials. A recent meta-analysis of those trials showed significantly fewer hemorrhagic strokes, fewer cardiovascular or unexplained deaths, and fewer nonprocedural bleeding events in Watchman recipients than in patients randomized to warfarin. And a cost-effectiveness analysis has concluded that after 8 years, the Watchman becomes “the dominant strategy” – meaning more effective and less costly for stroke prevention in patients with atrial fibrillation (AF) having a contraindication to warfarin – compared with the novel oral anticoagulant apixaban (J Am Coll Cardiol. 2015 Dec 22;66[24]:2728-39).

Moreover, the final pieces required for the Watchman to become a mainstream reimbursable therapy are falling into place. The Society for Cardiovascular Angiography and Interventions (SCAI), the American College of Cardiology, and the Heart Rhythm Society (HRS) have jointly issued institutional and operator requirements for left atrial appendage occlusion programs (J Am Coll Cardiol. 2015 Dec 8. pii: S0735-1097[15]07550-6). The ACC’s National Cardiovascular Data Registry has set up a new left atrial occlusion registry. And most important of all from a reimbursement standpoint, the Centers for Medicare and Medicaid Services has released a preliminary National Coverage Determination for left atrial appendage occlusion.

“This will affect your patients and your lives,” noted Dr. Holmes of the Mayo Clinic in Rochester, Minn. He and the Mayo Clinic share a financial interest in the Watchman technology, which has been licensed to Boston Scientific.

The CMS will cover the Watchman only when the catheter procedure is performed by an experienced interventional cardiologist or electrophysiologist in an experienced center as defined by the SCAI/ACC/HRS standards, and only in patients enrolled in the national prospective registry. The registry will monitor operator and device-related complications, stroke and systemic embolism rates, deaths, and major bleeding rates for 5 years post-procedure.

“If you want to be in this field, you will be in that registry because reimbursement will depend on that,” Dr. Holmes explained. “This registry will be incredibly important. It will tell us how we’re doing, what we should be doing, and what we could potentially be doing in the future.”

One hitch is that the preliminary National Coverage Determination states that coverage will be limited to AF patients with high stroke-risk and HAS-BLED scores as well as a contraindication to warfarin, whereas the FDA-approved indication says patients must be deemed by their physician to be suitable for warfarin.

“In this particular case, CMS was not talking with FDA. We don’t know how that will get sorted out,” according to the cardiologist. “But as soon as CMS comes through with their final regulatory coverage determination, I think we will finally be there. We’ll then be able to offer this as a treatment strategy for stroke prevention in selected patients with atrial fibrillation, realizing that with this device there’s a 40% reduction in the composite endpoint of cardiovascular or unexplained death, stroke, and systemic embolism compared to warfarin.”

That figure of a 40% relative risk reduction comes from the 46-month follow-up data in the randomized PROTECT AF trial (JAMA. 2014 Nov 19;312[19]:1988-98).

More recently, Dr. Holmes and his coinvestigators published a patient-level meta-analysis of data from PROTECT AF and PREVAIL, the other randomized trial of the Watchman versus warfarin. They reported that Watchman recipients had a 78% reduction in hemorrhagic strokes, a 52% reduction in cardiovascular or unexplained deaths, and a 49% lower rate of nonprocedural bleeding, compared with patients assigned to warfarin (J Am Coll Cardiol. 2015 Jun 23;65[24]:2614-23).

There have been no randomized trials comparing the Watchman to novel oral anticoagulants.

Dr. Holmes said the worldwide experience to date has been that roughly 95% of AF patients are able to safely go off warfarin or a novel oral anticoagulant 12 months after Watchman placement.

“So instead of taking eight drugs when you’re 75 years old, you can take seven. Most patients think that’s a pretty good deal,” the cardiologist observed.

Session moderator Dr. Samuel J. Asirvatham posed a question: Since recurrence of AF following catheter ablation is common and it’s now thought that up to 20% of AF arises from foci located in the left atrial appendage, what about combining standard catheter ablation of AF via pulmonary vein isolation with placement of the Watchman in a single procedure?

If such a combined procedure can be done efficiently, it should enable recipients of AF catheter ablation to safely go off oral anticoagulation, noted Dr. Asirvatham, an electrophysiologist who is professor of medicine and pediatrics at the Mayo Clinic, Rochester, Minn.

Dr. Holmes said several small studies of patients who have received combined AF ablation and Watchman implantation have been published.

“It’s uncertain whether left atrial appendage closure will affect AF recurrence rates post ablation, but it should reduce stroke risk. It’s a terribly important field of exploration that will be pursued in registries both in Europe and the United States,” he said.

[email protected]

SNOWMASS, COLO. – The goal is finally in sight following an odyssey to develop the Watchman left atrial appendage closure device as a safe and effective alternative to oral anticoagulation for stroke prevention in patients with nonvalvular atrial fibrillation, Dr. David R. Holmes Jr. said at the Annual Cardiovascular Conference at Snowmass.

It’s all coming together: The Watchman, a small percutaneously delivered parachute-like device, has received FDA marketing approval as the sole authorized left atrial appendage closure device in this country on the strength of two compellingly positive randomized controlled trials. A recent meta-analysis of those trials showed significantly fewer hemorrhagic strokes, fewer cardiovascular or unexplained deaths, and fewer nonprocedural bleeding events in Watchman recipients than in patients randomized to warfarin. And a cost-effectiveness analysis has concluded that after 8 years, the Watchman becomes “the dominant strategy” – meaning more effective and less costly for stroke prevention in patients with atrial fibrillation (AF) having a contraindication to warfarin – compared with the novel oral anticoagulant apixaban (J Am Coll Cardiol. 2015 Dec 22;66[24]:2728-39).

Moreover, the final pieces required for the Watchman to become a mainstream reimbursable therapy are falling into place. The Society for Cardiovascular Angiography and Interventions (SCAI), the American College of Cardiology, and the Heart Rhythm Society (HRS) have jointly issued institutional and operator requirements for left atrial appendage occlusion programs (J Am Coll Cardiol. 2015 Dec 8. pii: S0735-1097[15]07550-6). The ACC’s National Cardiovascular Data Registry has set up a new left atrial occlusion registry. And most important of all from a reimbursement standpoint, the Centers for Medicare and Medicaid Services has released a preliminary National Coverage Determination for left atrial appendage occlusion.

“This will affect your patients and your lives,” noted Dr. Holmes of the Mayo Clinic in Rochester, Minn. He and the Mayo Clinic share a financial interest in the Watchman technology, which has been licensed to Boston Scientific.

The CMS will cover the Watchman only when the catheter procedure is performed by an experienced interventional cardiologist or electrophysiologist in an experienced center as defined by the SCAI/ACC/HRS standards, and only in patients enrolled in the national prospective registry. The registry will monitor operator and device-related complications, stroke and systemic embolism rates, deaths, and major bleeding rates for 5 years post-procedure.

“If you want to be in this field, you will be in that registry because reimbursement will depend on that,” Dr. Holmes explained. “This registry will be incredibly important. It will tell us how we’re doing, what we should be doing, and what we could potentially be doing in the future.”

One hitch is that the preliminary National Coverage Determination states that coverage will be limited to AF patients with high stroke-risk and HAS-BLED scores as well as a contraindication to warfarin, whereas the FDA-approved indication says patients must be deemed by their physician to be suitable for warfarin.

“In this particular case, CMS was not talking with FDA. We don’t know how that will get sorted out,” according to the cardiologist. “But as soon as CMS comes through with their final regulatory coverage determination, I think we will finally be there. We’ll then be able to offer this as a treatment strategy for stroke prevention in selected patients with atrial fibrillation, realizing that with this device there’s a 40% reduction in the composite endpoint of cardiovascular or unexplained death, stroke, and systemic embolism compared to warfarin.”

That figure of a 40% relative risk reduction comes from the 46-month follow-up data in the randomized PROTECT AF trial (JAMA. 2014 Nov 19;312[19]:1988-98).

More recently, Dr. Holmes and his coinvestigators published a patient-level meta-analysis of data from PROTECT AF and PREVAIL, the other randomized trial of the Watchman versus warfarin. They reported that Watchman recipients had a 78% reduction in hemorrhagic strokes, a 52% reduction in cardiovascular or unexplained deaths, and a 49% lower rate of nonprocedural bleeding, compared with patients assigned to warfarin (J Am Coll Cardiol. 2015 Jun 23;65[24]:2614-23).

There have been no randomized trials comparing the Watchman to novel oral anticoagulants.

Dr. Holmes said the worldwide experience to date has been that roughly 95% of AF patients are able to safely go off warfarin or a novel oral anticoagulant 12 months after Watchman placement.

“So instead of taking eight drugs when you’re 75 years old, you can take seven. Most patients think that’s a pretty good deal,” the cardiologist observed.

Session moderator Dr. Samuel J. Asirvatham posed a question: Since recurrence of AF following catheter ablation is common and it’s now thought that up to 20% of AF arises from foci located in the left atrial appendage, what about combining standard catheter ablation of AF via pulmonary vein isolation with placement of the Watchman in a single procedure?

If such a combined procedure can be done efficiently, it should enable recipients of AF catheter ablation to safely go off oral anticoagulation, noted Dr. Asirvatham, an electrophysiologist who is professor of medicine and pediatrics at the Mayo Clinic, Rochester, Minn.

Dr. Holmes said several small studies of patients who have received combined AF ablation and Watchman implantation have been published.

“It’s uncertain whether left atrial appendage closure will affect AF recurrence rates post ablation, but it should reduce stroke risk. It’s a terribly important field of exploration that will be pursued in registries both in Europe and the United States,” he said.

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SNOWMASS, COLO. – The goal is finally in sight following an odyssey to develop the Watchman left atrial appendage closure device as a safe and effective alternative to oral anticoagulation for stroke prevention in patients with nonvalvular atrial fibrillation, Dr. David R. Holmes Jr. said at the Annual Cardiovascular Conference at Snowmass.

It’s all coming together: The Watchman, a small percutaneously delivered parachute-like device, has received FDA marketing approval as the sole authorized left atrial appendage closure device in this country on the strength of two compellingly positive randomized controlled trials. A recent meta-analysis of those trials showed significantly fewer hemorrhagic strokes, fewer cardiovascular or unexplained deaths, and fewer nonprocedural bleeding events in Watchman recipients than in patients randomized to warfarin. And a cost-effectiveness analysis has concluded that after 8 years, the Watchman becomes “the dominant strategy” – meaning more effective and less costly for stroke prevention in patients with atrial fibrillation (AF) having a contraindication to warfarin – compared with the novel oral anticoagulant apixaban (J Am Coll Cardiol. 2015 Dec 22;66[24]:2728-39).

Moreover, the final pieces required for the Watchman to become a mainstream reimbursable therapy are falling into place. The Society for Cardiovascular Angiography and Interventions (SCAI), the American College of Cardiology, and the Heart Rhythm Society (HRS) have jointly issued institutional and operator requirements for left atrial appendage occlusion programs (J Am Coll Cardiol. 2015 Dec 8. pii: S0735-1097[15]07550-6). The ACC’s National Cardiovascular Data Registry has set up a new left atrial occlusion registry. And most important of all from a reimbursement standpoint, the Centers for Medicare and Medicaid Services has released a preliminary National Coverage Determination for left atrial appendage occlusion.

“This will affect your patients and your lives,” noted Dr. Holmes of the Mayo Clinic in Rochester, Minn. He and the Mayo Clinic share a financial interest in the Watchman technology, which has been licensed to Boston Scientific.

The CMS will cover the Watchman only when the catheter procedure is performed by an experienced interventional cardiologist or electrophysiologist in an experienced center as defined by the SCAI/ACC/HRS standards, and only in patients enrolled in the national prospective registry. The registry will monitor operator and device-related complications, stroke and systemic embolism rates, deaths, and major bleeding rates for 5 years post-procedure.

“If you want to be in this field, you will be in that registry because reimbursement will depend on that,” Dr. Holmes explained. “This registry will be incredibly important. It will tell us how we’re doing, what we should be doing, and what we could potentially be doing in the future.”

One hitch is that the preliminary National Coverage Determination states that coverage will be limited to AF patients with high stroke-risk and HAS-BLED scores as well as a contraindication to warfarin, whereas the FDA-approved indication says patients must be deemed by their physician to be suitable for warfarin.

“In this particular case, CMS was not talking with FDA. We don’t know how that will get sorted out,” according to the cardiologist. “But as soon as CMS comes through with their final regulatory coverage determination, I think we will finally be there. We’ll then be able to offer this as a treatment strategy for stroke prevention in selected patients with atrial fibrillation, realizing that with this device there’s a 40% reduction in the composite endpoint of cardiovascular or unexplained death, stroke, and systemic embolism compared to warfarin.”

That figure of a 40% relative risk reduction comes from the 46-month follow-up data in the randomized PROTECT AF trial (JAMA. 2014 Nov 19;312[19]:1988-98).

More recently, Dr. Holmes and his coinvestigators published a patient-level meta-analysis of data from PROTECT AF and PREVAIL, the other randomized trial of the Watchman versus warfarin. They reported that Watchman recipients had a 78% reduction in hemorrhagic strokes, a 52% reduction in cardiovascular or unexplained deaths, and a 49% lower rate of nonprocedural bleeding, compared with patients assigned to warfarin (J Am Coll Cardiol. 2015 Jun 23;65[24]:2614-23).

There have been no randomized trials comparing the Watchman to novel oral anticoagulants.

Dr. Holmes said the worldwide experience to date has been that roughly 95% of AF patients are able to safely go off warfarin or a novel oral anticoagulant 12 months after Watchman placement.

“So instead of taking eight drugs when you’re 75 years old, you can take seven. Most patients think that’s a pretty good deal,” the cardiologist observed.

Session moderator Dr. Samuel J. Asirvatham posed a question: Since recurrence of AF following catheter ablation is common and it’s now thought that up to 20% of AF arises from foci located in the left atrial appendage, what about combining standard catheter ablation of AF via pulmonary vein isolation with placement of the Watchman in a single procedure?

If such a combined procedure can be done efficiently, it should enable recipients of AF catheter ablation to safely go off oral anticoagulation, noted Dr. Asirvatham, an electrophysiologist who is professor of medicine and pediatrics at the Mayo Clinic, Rochester, Minn.

Dr. Holmes said several small studies of patients who have received combined AF ablation and Watchman implantation have been published.

“It’s uncertain whether left atrial appendage closure will affect AF recurrence rates post ablation, but it should reduce stroke risk. It’s a terribly important field of exploration that will be pursued in registries both in Europe and the United States,” he said.

[email protected]