Conference Coverage

Two new approaches to surveillance imaging after treatment of stage I testicular seminoma sharply reduce or eliminate radiation exposure relative to the standard approach, without substantially compromising relapse detection, the phase 3 TRISST study suggests.

Results were reported at the 2021 Genitourinary Cancers Symposium (Abstract 374).

“Stage I seminoma has a survival that approaches 100%. Over recent years, CT surveillance has become an international standard of care and has largely replaced the use of adjuvant treatment,” said investigator Robert A. Huddart, MRCP, FRCR, PhD, of The Royal Marsden NHS Foundation Trust, London.

“A typical surveillance protocol, however, consists of multiple CT scans taken over a period of a few years and results in quite a high diagnostic radiation dose, which has raised questions about the long-term risk of second malignancies related to this program,” he noted. “At the moment, there is no evidence base to inform how frequently imaging should be undertaken and the type of imaging that should be used.”

Results of TRISST showed that, with a median 6-year follow-up during which men were monitored with various surveillance protocols, 1.5% experienced a relapse that was advanced (stage IIC or higher) at detection.

The incidence of relapse was 0.3% with the standard schedule of seven abdominal surveillance scans and a statistically noninferior 2.8% with three more widely spaced scans. Also, compared with the standard CT scans, which yielded an incidence of 2.6%, MRI scans were noninferior, yielding an incidence of 0.6%.

“The three-scan schedule was noninferior to seven scans in our protocol, and in fact, with the three-scan schedule, we would use over 1,000 fewer scans at a cost of perhaps having four relapses that could have been avoided,” Dr. Huddart pointed out. “We can conclude that MRI is noninferior to CT and should be recommended to avoid irradiation. This study will provide an evidence base for making the transition to MRI, which is important. The MRI scan is more complex – it takes longer and is more resource heavy. So we do need to supply the evidence that it is the right thing to do for patients.”

Need for expertise in interpreting MRI scans is a valid concern, he acknowledged. “There is a degree of specialization in the UK for testis cancer management, and clearly, you had to be specialist to take part in the study. So I can’t say it is your everyday radiologist, but the data would suggest we actually saw less errors in terms of pickup with the MRI scan than with the CT scan,” he said. “You do need to have a level of expertise, but it doesn’t require super-specialist expertise. I suppose that will be a learning lesson for all of us, to learn better MRI interpretation if we are using MRI.”
 

Trial details

The 669 men randomized in TRISST (NCT00589537), a multicenter trial with a factorial and noninferiority design, had undergone orchiectomy for stage I seminoma and did not have any adjuvant therapy planned.

They were randomized once on number of surveillance scans: seven scans (at 6, 12, 18, 24, 36, 48, and 60 months) vs. three scans (at 6, 18, and 36 months). And they were randomized again on scan modality: CT versus MRI. All groups had similar follow-up otherwise, consisting of periodic chest radiographs, tumor marker tests, and clinical assessments.

The primary outcome, 6-year incidence of advanced relapse defined as stage IIC or higher (i.e., measuring 5 cm or greater) by Royal Marsden Hospital criteria, was chosen because, when the study began, this was the dividing point between using local therapy and using systemic multiagent chemotherapy to treat a relapse, Dr. Huddart explained.

Among men remaining on surveillance, compliance was good, with 94% of all scans attended and 79% performed on time, he reported.

Overall, 12% of the randomized population experienced a relapse of any stage during follow-up, with nearly all relapses occurring within the first 3 years.

The 6-year incidence of advanced relapse was just 1.5% in the entire trial population, lower than the 5.7% expected in trial planning, according to Dr. Huddart.

In intention-to-treat analyses, the incidence was 2.8% with the three-scan schedule and 0.3% with the seven-scan schedule, with the difference of 2.6% and the bounds of the 90% confidence interval falling within the predefined noninferiority margin of 5.7%.

Using three scans instead of seven scans increased the proportion of patients with relapse who had advanced stage from 3% to 20%. Four of the nine advanced relapses occurring with the three-scan schedule could possibly have been detected earlier with the seven-scan schedule.

The 6-year incidence of advanced relapse was 0.6% with MRI scans and 2.6% with CT scans. The difference of –1.9% and the bounds of the 90% confidence interval fell within the noninferiority margin. Use of MRI instead of CT reduced the proportion of patients with relapse who had advanced stage from 20% to 5%.

For both the scan frequency comparison and the scan modality comparison, findings were essentially the same in per protocol analyses and in analyses that instead looked at relapses measuring 3 cm or greater, according to Dr. Huddart.

Fully 89% of patients with advanced relapses were treated with chemotherapy only, and 56% of all patients with advanced relapse had a response to their treatment.

Most patients experiencing a relapse of any stage, 93%, were alive and free of disease at their most recent follow-up, Dr. Huddart reported. Overall survival for the trial population was 99% and similar across surveillance groups, with no deaths due to testicular cancer.
 

Risk-tailored surveillance

“Noninferiority trials are much more challenging than equivalence or superiority trials,” observed invited discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University, Turkey.

She expressed some reservations about TRISST results, including the much lower than expected incidence of advanced relapse, which may have affected comparisons, and problematic compliance, as about one-quarter of patients stopped surveillance before relapse or withdrew from the trial before 6 years of follow-up.

Recurrence after treatment of stage I seminoma is largely driven by the risk factors of tumor size exceeding 4 cm and presence of rete testis invasion, and 54% of TRISST patients did not have either of these factors, Dr. Laguna noted.

“While a more relaxed schedule may well suit those patients at low risk, more intense schedules will be appropriate for patients with risk factors,” she maintained. “I am pretty sure that the TRISST trial will impact future guideline recommendations, although still I think that one approach may not fit all.”

TRISST was funded by Cancer Research UK and the MRC Clinical Trials Unit. Dr. Huddart disclosed relationships with Janssen Oncology, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Nektar, and Roche. Dr. Laguna disclosed that she is chair of the EAU Testicular Cancer Guidelines Panel.

Two new approaches to surveillance imaging after treatment of stage I testicular seminoma sharply reduce or eliminate radiation exposure relative to the standard approach, without substantially compromising relapse detection, the phase 3 TRISST study suggests.

Results were reported at the 2021 Genitourinary Cancers Symposium (Abstract 374).

“Stage I seminoma has a survival that approaches 100%. Over recent years, CT surveillance has become an international standard of care and has largely replaced the use of adjuvant treatment,” said investigator Robert A. Huddart, MRCP, FRCR, PhD, of The Royal Marsden NHS Foundation Trust, London.

“A typical surveillance protocol, however, consists of multiple CT scans taken over a period of a few years and results in quite a high diagnostic radiation dose, which has raised questions about the long-term risk of second malignancies related to this program,” he noted. “At the moment, there is no evidence base to inform how frequently imaging should be undertaken and the type of imaging that should be used.”

Results of TRISST showed that, with a median 6-year follow-up during which men were monitored with various surveillance protocols, 1.5% experienced a relapse that was advanced (stage IIC or higher) at detection.

The incidence of relapse was 0.3% with the standard schedule of seven abdominal surveillance scans and a statistically noninferior 2.8% with three more widely spaced scans. Also, compared with the standard CT scans, which yielded an incidence of 2.6%, MRI scans were noninferior, yielding an incidence of 0.6%.

“The three-scan schedule was noninferior to seven scans in our protocol, and in fact, with the three-scan schedule, we would use over 1,000 fewer scans at a cost of perhaps having four relapses that could have been avoided,” Dr. Huddart pointed out. “We can conclude that MRI is noninferior to CT and should be recommended to avoid irradiation. This study will provide an evidence base for making the transition to MRI, which is important. The MRI scan is more complex – it takes longer and is more resource heavy. So we do need to supply the evidence that it is the right thing to do for patients.”

Need for expertise in interpreting MRI scans is a valid concern, he acknowledged. “There is a degree of specialization in the UK for testis cancer management, and clearly, you had to be specialist to take part in the study. So I can’t say it is your everyday radiologist, but the data would suggest we actually saw less errors in terms of pickup with the MRI scan than with the CT scan,” he said. “You do need to have a level of expertise, but it doesn’t require super-specialist expertise. I suppose that will be a learning lesson for all of us, to learn better MRI interpretation if we are using MRI.”
 

Trial details

The 669 men randomized in TRISST (NCT00589537), a multicenter trial with a factorial and noninferiority design, had undergone orchiectomy for stage I seminoma and did not have any adjuvant therapy planned.

They were randomized once on number of surveillance scans: seven scans (at 6, 12, 18, 24, 36, 48, and 60 months) vs. three scans (at 6, 18, and 36 months). And they were randomized again on scan modality: CT versus MRI. All groups had similar follow-up otherwise, consisting of periodic chest radiographs, tumor marker tests, and clinical assessments.

The primary outcome, 6-year incidence of advanced relapse defined as stage IIC or higher (i.e., measuring 5 cm or greater) by Royal Marsden Hospital criteria, was chosen because, when the study began, this was the dividing point between using local therapy and using systemic multiagent chemotherapy to treat a relapse, Dr. Huddart explained.

Among men remaining on surveillance, compliance was good, with 94% of all scans attended and 79% performed on time, he reported.

Overall, 12% of the randomized population experienced a relapse of any stage during follow-up, with nearly all relapses occurring within the first 3 years.

The 6-year incidence of advanced relapse was just 1.5% in the entire trial population, lower than the 5.7% expected in trial planning, according to Dr. Huddart.

In intention-to-treat analyses, the incidence was 2.8% with the three-scan schedule and 0.3% with the seven-scan schedule, with the difference of 2.6% and the bounds of the 90% confidence interval falling within the predefined noninferiority margin of 5.7%.

Using three scans instead of seven scans increased the proportion of patients with relapse who had advanced stage from 3% to 20%. Four of the nine advanced relapses occurring with the three-scan schedule could possibly have been detected earlier with the seven-scan schedule.

The 6-year incidence of advanced relapse was 0.6% with MRI scans and 2.6% with CT scans. The difference of –1.9% and the bounds of the 90% confidence interval fell within the noninferiority margin. Use of MRI instead of CT reduced the proportion of patients with relapse who had advanced stage from 20% to 5%.

For both the scan frequency comparison and the scan modality comparison, findings were essentially the same in per protocol analyses and in analyses that instead looked at relapses measuring 3 cm or greater, according to Dr. Huddart.

Fully 89% of patients with advanced relapses were treated with chemotherapy only, and 56% of all patients with advanced relapse had a response to their treatment.

Most patients experiencing a relapse of any stage, 93%, were alive and free of disease at their most recent follow-up, Dr. Huddart reported. Overall survival for the trial population was 99% and similar across surveillance groups, with no deaths due to testicular cancer.
 

Risk-tailored surveillance

“Noninferiority trials are much more challenging than equivalence or superiority trials,” observed invited discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University, Turkey.

She expressed some reservations about TRISST results, including the much lower than expected incidence of advanced relapse, which may have affected comparisons, and problematic compliance, as about one-quarter of patients stopped surveillance before relapse or withdrew from the trial before 6 years of follow-up.

Recurrence after treatment of stage I seminoma is largely driven by the risk factors of tumor size exceeding 4 cm and presence of rete testis invasion, and 54% of TRISST patients did not have either of these factors, Dr. Laguna noted.

“While a more relaxed schedule may well suit those patients at low risk, more intense schedules will be appropriate for patients with risk factors,” she maintained. “I am pretty sure that the TRISST trial will impact future guideline recommendations, although still I think that one approach may not fit all.”

TRISST was funded by Cancer Research UK and the MRC Clinical Trials Unit. Dr. Huddart disclosed relationships with Janssen Oncology, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Nektar, and Roche. Dr. Laguna disclosed that she is chair of the EAU Testicular Cancer Guidelines Panel.

Two new approaches to surveillance imaging after treatment of stage I testicular seminoma sharply reduce or eliminate radiation exposure relative to the standard approach, without substantially compromising relapse detection, the phase 3 TRISST study suggests.

Results were reported at the 2021 Genitourinary Cancers Symposium (Abstract 374).

“Stage I seminoma has a survival that approaches 100%. Over recent years, CT surveillance has become an international standard of care and has largely replaced the use of adjuvant treatment,” said investigator Robert A. Huddart, MRCP, FRCR, PhD, of The Royal Marsden NHS Foundation Trust, London.

“A typical surveillance protocol, however, consists of multiple CT scans taken over a period of a few years and results in quite a high diagnostic radiation dose, which has raised questions about the long-term risk of second malignancies related to this program,” he noted. “At the moment, there is no evidence base to inform how frequently imaging should be undertaken and the type of imaging that should be used.”

Results of TRISST showed that, with a median 6-year follow-up during which men were monitored with various surveillance protocols, 1.5% experienced a relapse that was advanced (stage IIC or higher) at detection.

The incidence of relapse was 0.3% with the standard schedule of seven abdominal surveillance scans and a statistically noninferior 2.8% with three more widely spaced scans. Also, compared with the standard CT scans, which yielded an incidence of 2.6%, MRI scans were noninferior, yielding an incidence of 0.6%.

“The three-scan schedule was noninferior to seven scans in our protocol, and in fact, with the three-scan schedule, we would use over 1,000 fewer scans at a cost of perhaps having four relapses that could have been avoided,” Dr. Huddart pointed out. “We can conclude that MRI is noninferior to CT and should be recommended to avoid irradiation. This study will provide an evidence base for making the transition to MRI, which is important. The MRI scan is more complex – it takes longer and is more resource heavy. So we do need to supply the evidence that it is the right thing to do for patients.”

Need for expertise in interpreting MRI scans is a valid concern, he acknowledged. “There is a degree of specialization in the UK for testis cancer management, and clearly, you had to be specialist to take part in the study. So I can’t say it is your everyday radiologist, but the data would suggest we actually saw less errors in terms of pickup with the MRI scan than with the CT scan,” he said. “You do need to have a level of expertise, but it doesn’t require super-specialist expertise. I suppose that will be a learning lesson for all of us, to learn better MRI interpretation if we are using MRI.”
 

Trial details

The 669 men randomized in TRISST (NCT00589537), a multicenter trial with a factorial and noninferiority design, had undergone orchiectomy for stage I seminoma and did not have any adjuvant therapy planned.

They were randomized once on number of surveillance scans: seven scans (at 6, 12, 18, 24, 36, 48, and 60 months) vs. three scans (at 6, 18, and 36 months). And they were randomized again on scan modality: CT versus MRI. All groups had similar follow-up otherwise, consisting of periodic chest radiographs, tumor marker tests, and clinical assessments.

The primary outcome, 6-year incidence of advanced relapse defined as stage IIC or higher (i.e., measuring 5 cm or greater) by Royal Marsden Hospital criteria, was chosen because, when the study began, this was the dividing point between using local therapy and using systemic multiagent chemotherapy to treat a relapse, Dr. Huddart explained.

Among men remaining on surveillance, compliance was good, with 94% of all scans attended and 79% performed on time, he reported.

Overall, 12% of the randomized population experienced a relapse of any stage during follow-up, with nearly all relapses occurring within the first 3 years.

The 6-year incidence of advanced relapse was just 1.5% in the entire trial population, lower than the 5.7% expected in trial planning, according to Dr. Huddart.

In intention-to-treat analyses, the incidence was 2.8% with the three-scan schedule and 0.3% with the seven-scan schedule, with the difference of 2.6% and the bounds of the 90% confidence interval falling within the predefined noninferiority margin of 5.7%.

Using three scans instead of seven scans increased the proportion of patients with relapse who had advanced stage from 3% to 20%. Four of the nine advanced relapses occurring with the three-scan schedule could possibly have been detected earlier with the seven-scan schedule.

The 6-year incidence of advanced relapse was 0.6% with MRI scans and 2.6% with CT scans. The difference of –1.9% and the bounds of the 90% confidence interval fell within the noninferiority margin. Use of MRI instead of CT reduced the proportion of patients with relapse who had advanced stage from 20% to 5%.

For both the scan frequency comparison and the scan modality comparison, findings were essentially the same in per protocol analyses and in analyses that instead looked at relapses measuring 3 cm or greater, according to Dr. Huddart.

Fully 89% of patients with advanced relapses were treated with chemotherapy only, and 56% of all patients with advanced relapse had a response to their treatment.

Most patients experiencing a relapse of any stage, 93%, were alive and free of disease at their most recent follow-up, Dr. Huddart reported. Overall survival for the trial population was 99% and similar across surveillance groups, with no deaths due to testicular cancer.
 

Risk-tailored surveillance

“Noninferiority trials are much more challenging than equivalence or superiority trials,” observed invited discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University, Turkey.

She expressed some reservations about TRISST results, including the much lower than expected incidence of advanced relapse, which may have affected comparisons, and problematic compliance, as about one-quarter of patients stopped surveillance before relapse or withdrew from the trial before 6 years of follow-up.

Recurrence after treatment of stage I seminoma is largely driven by the risk factors of tumor size exceeding 4 cm and presence of rete testis invasion, and 54% of TRISST patients did not have either of these factors, Dr. Laguna noted.

“While a more relaxed schedule may well suit those patients at low risk, more intense schedules will be appropriate for patients with risk factors,” she maintained. “I am pretty sure that the TRISST trial will impact future guideline recommendations, although still I think that one approach may not fit all.”

TRISST was funded by Cancer Research UK and the MRC Clinical Trials Unit. Dr. Huddart disclosed relationships with Janssen Oncology, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Nektar, and Roche. Dr. Laguna disclosed that she is chair of the EAU Testicular Cancer Guidelines Panel.

Researchers have come a long way in understanding the link between acute inflammation and treatment-resistant depression, but more work needs to be done, according to Mark Hyman Rapaport, MD.

Svisio/Thinkstock

“Inflammation has been a hot topic in the past decade, both because of its impact in medical disorders and in psychiatric disorders,” Dr. Rapaport, CEO of the Huntsman Mental Health Institute in Salt Lake City, Utah, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “We run into difficulty with chronic inflammation, which we see with rheumatic disorders, and when we think of metabolic syndrome and obesity.”

The immune system helps to control energy regulation and neuroendocrine function in acute inflammation and chronic inflammatory diseases. “We see a variety of effects on the central nervous system or liver function or on homeostasis of the body,” said Dr. Rapaport, who also chairs the department of psychiatry at the University of Utah, also in Salt Lake City. “These are all normal and necessary to channel energy to the immune system in order to fight what’s necessary in acute inflammatory response.”

A chronic state of inflammation can result in prolonged allocation of fuels to the immune system, tissue inflammation, and a chronically aberrant immune reaction, he continued. This can cause depressive symptoms/fatigue, anorexia, malnutrition, muscle wasting, cachectic obesity, insulin resistance, dyslipidemia, increased adipose tissue in the proximity of inflammatory lesion, alterations of steroid hormone axes, elevated sympathetic tone, hypertension, decreased parasympathetic tone, inflammation-related anemia, and osteopenia. “So, chronic inflammation has a lot of long-term sequelae that are detrimental,” he said.

Both physical stress and psychological stress also cause an inflammatory state. After looking at the medical literature, Dr. Rapaport and colleagues began to wonder whether inflammation and immune activation associated with psychiatric disorders are attributable to the stress of acute illness. To find out, they performed a meta-analysis of blood cytokine network alterations in psychiatric patients and evaluated comparisons between schizophrenia, bipolar disorder, and depression. A total of three meta-analyses were performed: one of acute/inpatient studies, one on the impact of acute treatment, and one of outpatient studies. The researchers hypothesized that inflammatory and immune findings in psychiatric illnesses were tied to two distinct etiologies: the acute stress of illness and intrinsic immune dysfunction.

The meta-analyses included 68 studies: 40 involving patients with schizophrenia, 18 involving those with major depressive disorder (MDD) and 10 involving those with bipolar disorder. The researchers found that levels of four cytokines were significantly increased in acutely ill patients with schizophrenia, bipolar mania, and MDD, compared with controls: interleukin-6, tumor necrosis factor–alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), and IL-1 receptor antagonist (IL-1RA). “There has not been a consistent blood panel used across studies, be it within a disorder itself like depression, or across disorders,” Dr. Rapaport noted. “This is a challenge that we face in looking at these data.”

Following treatment of acute illness, IL-6 levels significantly decreased in schizophrenia and MDD, but no significant changes in TNF-alpha levels were observed in patients with schizophrenia or MDD. In addition, sIL-2R levels increase in schizophrenia but remained unchanged in bipolar and MDD, while IL-1RA levels in bipolar mania decreased but remained unchanged in MDD. Meanwhile, assessment of the study’s 24 outpatient studies revealed that levels of IL-6 were significantly increased in outpatients with schizophrenia, euthymic bipolar disorder, and MDD, compared with controls (P < .01 for each). In addition, levels of IL-1 beta and sIL-2R were significantly increased in outpatients with schizophrenia and bipolar disorder.

According to Dr. Rapaport, these meta-analyses suggest that there are likely inflammatory immune findings present in acutely ill patients with MDD, schizophrenia, and bipolar disorder.

“Some of this activation decreases with effective acute treatment of the disorder,” he said. “The data suggest that immune changes are present in a subset of patients with all three disorders.”

Advancing this area of research requires a better understanding of the bidirectional interactions between the brain and periphery. “We also need to understand the regulatory role that microglia and astroglia play within the brain,” he said. “We need to identify changes in brain circuitry and function associated with inflammation and other immune changes. We also need to carefully scrutinize publications, understand the assumptions behind the statistics, and carry out more research beyond the protein level.”

He concluded his presentation by calling for research to help clinicians differentiate acute from chronic inflammation. “The study of both is important,” he said. “We need to understand the pathophysiology of immune changes in psychiatric disorders. We need to study both the triggers and pathways to resolution.”

Dr. Rapaport disclosed that he has received research support from the National Institutes of Health, the National Institute of Mental Health, and the National Center for Complementary and Integrative Health.

dbrunk@mdedge.com

Researchers have come a long way in understanding the link between acute inflammation and treatment-resistant depression, but more work needs to be done, according to Mark Hyman Rapaport, MD.

Svisio/Thinkstock

“Inflammation has been a hot topic in the past decade, both because of its impact in medical disorders and in psychiatric disorders,” Dr. Rapaport, CEO of the Huntsman Mental Health Institute in Salt Lake City, Utah, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “We run into difficulty with chronic inflammation, which we see with rheumatic disorders, and when we think of metabolic syndrome and obesity.”

The immune system helps to control energy regulation and neuroendocrine function in acute inflammation and chronic inflammatory diseases. “We see a variety of effects on the central nervous system or liver function or on homeostasis of the body,” said Dr. Rapaport, who also chairs the department of psychiatry at the University of Utah, also in Salt Lake City. “These are all normal and necessary to channel energy to the immune system in order to fight what’s necessary in acute inflammatory response.”

A chronic state of inflammation can result in prolonged allocation of fuels to the immune system, tissue inflammation, and a chronically aberrant immune reaction, he continued. This can cause depressive symptoms/fatigue, anorexia, malnutrition, muscle wasting, cachectic obesity, insulin resistance, dyslipidemia, increased adipose tissue in the proximity of inflammatory lesion, alterations of steroid hormone axes, elevated sympathetic tone, hypertension, decreased parasympathetic tone, inflammation-related anemia, and osteopenia. “So, chronic inflammation has a lot of long-term sequelae that are detrimental,” he said.

Both physical stress and psychological stress also cause an inflammatory state. After looking at the medical literature, Dr. Rapaport and colleagues began to wonder whether inflammation and immune activation associated with psychiatric disorders are attributable to the stress of acute illness. To find out, they performed a meta-analysis of blood cytokine network alterations in psychiatric patients and evaluated comparisons between schizophrenia, bipolar disorder, and depression. A total of three meta-analyses were performed: one of acute/inpatient studies, one on the impact of acute treatment, and one of outpatient studies. The researchers hypothesized that inflammatory and immune findings in psychiatric illnesses were tied to two distinct etiologies: the acute stress of illness and intrinsic immune dysfunction.

The meta-analyses included 68 studies: 40 involving patients with schizophrenia, 18 involving those with major depressive disorder (MDD) and 10 involving those with bipolar disorder. The researchers found that levels of four cytokines were significantly increased in acutely ill patients with schizophrenia, bipolar mania, and MDD, compared with controls: interleukin-6, tumor necrosis factor–alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), and IL-1 receptor antagonist (IL-1RA). “There has not been a consistent blood panel used across studies, be it within a disorder itself like depression, or across disorders,” Dr. Rapaport noted. “This is a challenge that we face in looking at these data.”

Following treatment of acute illness, IL-6 levels significantly decreased in schizophrenia and MDD, but no significant changes in TNF-alpha levels were observed in patients with schizophrenia or MDD. In addition, sIL-2R levels increase in schizophrenia but remained unchanged in bipolar and MDD, while IL-1RA levels in bipolar mania decreased but remained unchanged in MDD. Meanwhile, assessment of the study’s 24 outpatient studies revealed that levels of IL-6 were significantly increased in outpatients with schizophrenia, euthymic bipolar disorder, and MDD, compared with controls (P < .01 for each). In addition, levels of IL-1 beta and sIL-2R were significantly increased in outpatients with schizophrenia and bipolar disorder.

According to Dr. Rapaport, these meta-analyses suggest that there are likely inflammatory immune findings present in acutely ill patients with MDD, schizophrenia, and bipolar disorder.

“Some of this activation decreases with effective acute treatment of the disorder,” he said. “The data suggest that immune changes are present in a subset of patients with all three disorders.”

Advancing this area of research requires a better understanding of the bidirectional interactions between the brain and periphery. “We also need to understand the regulatory role that microglia and astroglia play within the brain,” he said. “We need to identify changes in brain circuitry and function associated with inflammation and other immune changes. We also need to carefully scrutinize publications, understand the assumptions behind the statistics, and carry out more research beyond the protein level.”

He concluded his presentation by calling for research to help clinicians differentiate acute from chronic inflammation. “The study of both is important,” he said. “We need to understand the pathophysiology of immune changes in psychiatric disorders. We need to study both the triggers and pathways to resolution.”

Dr. Rapaport disclosed that he has received research support from the National Institutes of Health, the National Institute of Mental Health, and the National Center for Complementary and Integrative Health.

dbrunk@mdedge.com

Researchers have come a long way in understanding the link between acute inflammation and treatment-resistant depression, but more work needs to be done, according to Mark Hyman Rapaport, MD.

Svisio/Thinkstock

“Inflammation has been a hot topic in the past decade, both because of its impact in medical disorders and in psychiatric disorders,” Dr. Rapaport, CEO of the Huntsman Mental Health Institute in Salt Lake City, Utah, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “We run into difficulty with chronic inflammation, which we see with rheumatic disorders, and when we think of metabolic syndrome and obesity.”

The immune system helps to control energy regulation and neuroendocrine function in acute inflammation and chronic inflammatory diseases. “We see a variety of effects on the central nervous system or liver function or on homeostasis of the body,” said Dr. Rapaport, who also chairs the department of psychiatry at the University of Utah, also in Salt Lake City. “These are all normal and necessary to channel energy to the immune system in order to fight what’s necessary in acute inflammatory response.”

A chronic state of inflammation can result in prolonged allocation of fuels to the immune system, tissue inflammation, and a chronically aberrant immune reaction, he continued. This can cause depressive symptoms/fatigue, anorexia, malnutrition, muscle wasting, cachectic obesity, insulin resistance, dyslipidemia, increased adipose tissue in the proximity of inflammatory lesion, alterations of steroid hormone axes, elevated sympathetic tone, hypertension, decreased parasympathetic tone, inflammation-related anemia, and osteopenia. “So, chronic inflammation has a lot of long-term sequelae that are detrimental,” he said.

Both physical stress and psychological stress also cause an inflammatory state. After looking at the medical literature, Dr. Rapaport and colleagues began to wonder whether inflammation and immune activation associated with psychiatric disorders are attributable to the stress of acute illness. To find out, they performed a meta-analysis of blood cytokine network alterations in psychiatric patients and evaluated comparisons between schizophrenia, bipolar disorder, and depression. A total of three meta-analyses were performed: one of acute/inpatient studies, one on the impact of acute treatment, and one of outpatient studies. The researchers hypothesized that inflammatory and immune findings in psychiatric illnesses were tied to two distinct etiologies: the acute stress of illness and intrinsic immune dysfunction.

The meta-analyses included 68 studies: 40 involving patients with schizophrenia, 18 involving those with major depressive disorder (MDD) and 10 involving those with bipolar disorder. The researchers found that levels of four cytokines were significantly increased in acutely ill patients with schizophrenia, bipolar mania, and MDD, compared with controls: interleukin-6, tumor necrosis factor–alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), and IL-1 receptor antagonist (IL-1RA). “There has not been a consistent blood panel used across studies, be it within a disorder itself like depression, or across disorders,” Dr. Rapaport noted. “This is a challenge that we face in looking at these data.”

Following treatment of acute illness, IL-6 levels significantly decreased in schizophrenia and MDD, but no significant changes in TNF-alpha levels were observed in patients with schizophrenia or MDD. In addition, sIL-2R levels increase in schizophrenia but remained unchanged in bipolar and MDD, while IL-1RA levels in bipolar mania decreased but remained unchanged in MDD. Meanwhile, assessment of the study’s 24 outpatient studies revealed that levels of IL-6 were significantly increased in outpatients with schizophrenia, euthymic bipolar disorder, and MDD, compared with controls (P < .01 for each). In addition, levels of IL-1 beta and sIL-2R were significantly increased in outpatients with schizophrenia and bipolar disorder.

According to Dr. Rapaport, these meta-analyses suggest that there are likely inflammatory immune findings present in acutely ill patients with MDD, schizophrenia, and bipolar disorder.

“Some of this activation decreases with effective acute treatment of the disorder,” he said. “The data suggest that immune changes are present in a subset of patients with all three disorders.”

Advancing this area of research requires a better understanding of the bidirectional interactions between the brain and periphery. “We also need to understand the regulatory role that microglia and astroglia play within the brain,” he said. “We need to identify changes in brain circuitry and function associated with inflammation and other immune changes. We also need to carefully scrutinize publications, understand the assumptions behind the statistics, and carry out more research beyond the protein level.”

He concluded his presentation by calling for research to help clinicians differentiate acute from chronic inflammation. “The study of both is important,” he said. “We need to understand the pathophysiology of immune changes in psychiatric disorders. We need to study both the triggers and pathways to resolution.”

Dr. Rapaport disclosed that he has received research support from the National Institutes of Health, the National Institute of Mental Health, and the National Center for Complementary and Integrative Health.

dbrunk@mdedge.com

Rheumatologists can look forward to the likely regulatory approval of the oral Janus kinase inhibitors tofacitinib and upadacitinib for the treatment of axial spondyloarthritis in the first half of 2021, speakers predicted at the 2021 Rheumatology Winter Clinical Symposium.

This will be a major advance in the treatment of axial spondyloarthritis (axSpA) and promises to be one of the overall highlights of the coming year in rheumatology, according to the speakers. Both medications are now under Food and Drug Administration review for the proposed new indication.

“My sense is within the next 6 months we’re going to have two different oral JAK inhibitors that offer a new option for our ankylosing spondylitis and axial spondyloarthritis patients,” predicted Eric M. Ruderman, MD, professor of medicine (rheumatology) at Northwestern University, Chicago.

Alexis R. Ogdie, MD, MSCE, noted that, at present, only two classes of potent medications are available for treatment of axial spondyloarthritis: tumor necrosis factor (TNF) inhibitors and anti–interleukin-17 biologics.

“I think it would be so exciting to have more treatment options. To have only two classes of drugs you can use for this disease is not enough,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.

She and her fellow panelists also highlighted other recent key developments in axSpA, including epidemiologic evidence that case numbers are climbing sharply, identification of two previously unrecognized common comorbidities, a successful biologic remission induction and maintenance dose–reduction strategy, data on the best and worst biologics for patients with anterior uveitis, and evidence regarding next-step therapy in axSpA patients who’ve had an inadequate response to a TNF inhibitor.
 

The JAK inhibitors are coming

Oral tofacitinib (Xeljanz) at 5 mg twice daily was the focus of a pivotal phase 3, double-blind, 16-week, placebo-controlled clinical trial including 269 patients with axSpA. The results were presented at the 2020 annual meeting of the American College of Rheumatology. The primary endpoint was at least a 20% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 20). This was accomplished in 56.4% of patients on tofacitinib and 29.4% of placebo-treated controls. The ASAS 40 response rate was even more impressive: 40.6% with the JAK inhibitor, compared with 12.5% with placebo. There was one serious infection in the tofacitinib group, but no cases of venous thromboembolism, interstitial lung disease, opportunistic infection, major adverse cardiovascular events, or malignancy in this brief 4-month study.

Also now under FDA review are data from SELECT-AXIS 1, a phase 2/3, double-blind trial in which 187 biologic-naive patients with ankylosing spondylitis were randomized to 14 weeks of upadacitinib (Rinvoq) at 15 mg once daily or placebo. The primary endpoint, an ASAS 40 response, occurred in 51.6% of patients on the JAK inhibitor and half as many controls.

“They saw improvement in MRI scores with upadacitinib, so there’s biologic plausibility to this,” Dr. Ruderman noted.

He predicted the JAK inhibitors are going to have a big impact in clinical practice, especially in men.

“I have a lot of ankylosing spondylitis and axial spondyloarthritis patients on NSAIDs who I’m not convinced are doing as well as they could, but they push back every time I raise the possibility of going on a biologic,” the rheumatologist said. “I suspect that, given the rapid response with JAK inhibitors here, as in rheumatoid arthritis, it might be a little bit easier to persuade these people to give this a try for 4-6 weeks and then see how much better they are. It’s a pill. You don’t have to give yourself a shot.”

Dr. Ogdie predicted the new oral agents will bring more axSpA patients into rheumatologists’ offices.

“I think it’ll be kind of like the apremilast effect in psoriasis, where the drug got a lot more people into the market,” she said.

U.S. ankylosing spondylitis prevalence rising

The diagnostic prevalence of axSpA in the United States increased by 86% between 2006 and 2014 in a retrospective analysis based on Medicare fee-for-service claims data. A separate analysis using IBM MarketScan data for the same years was confirmatory, showing a 56% increase, Jeffrey R. Curtis, MD, MS, MPH, of the University of Alabama at Birmingham reported at the 2020 annual meeting of the European League Against Rheumatism (EULAR), now known as the European Alliance of Associations for Rheumatology.

“I think the take home is we’re seeing more of this. Some of this is likely due to increased awareness and inclusion of nonradiographic disease,” according to Dr. Ruderman.
 

Two previously overlooked comorbidities

It’s well recognized that 5%-10% of patients with axSpA have concurrent inflammatory bowel disease. But how about irritable bowel syndrome (IBS)?

A study of 186 Swedish patients with axSpA in the population-based SPARTAKUS registry, none with inflammatory bowel disease, concluded that 30% of them met ROME III diagnostic criteria for IBS, compared with 16% of healthy controls. Of note, the axSpA patients with comorbid IBS had significantly worse axSpA disease outcomes, compared with those without IBS as measured by pain, fatigue, and quality-of-life scores, as well as significantly greater disease activity on the Bath Ankylosing Spondylitis Disease Activity Index.

New-onset inflammatory back pain occurred in a hefty 24% of 513 Saudi patients placed on isotretinoin for acne. About 42% of those with inflammatory back pain displayed evidence of sacroiliitis on MRI. Moreover, 52% of patients with MRI-proven sacroiliitis fulfilled ASAS criteria for axSpA. In this longitudinal study, the MRI abnormalities and back pain symptoms completely resolved after isotretinoin discontinuation, but it took a long time: up to 9 months.

“When you see these people with inflammatory back pain on isotretinoin, I think it’s important that before you saddle them with a diagnosis that they have axSpA – a diagnosis that will go with them forever – give them time off drug, because this can look like the real thing. It’s something to think about as these pretty young kids come in to see you with back pain: Always ask about their medication history because it could be important,” Dr. Ruderman said.

A successful biologic remission induction-and-maintenance strategy

The phase 3b, multicenter C-OPTIMISE study sought to determine the best strategy for avoiding axSpA flares once sustained clinical remission has been achieved with a TNF inhibitor, in this case certolizumab pegol (Cimzia). The first part of the trial involved 736 patients with early axSpA, including 329 with nonradiographic disease. During the 48-week open-label induction period, 43.9% of patients achieved sustained clinical remission at the approved dose of 200 mg every 2 weeks, with similar success rates in radiographic and nonradiographic axSpA.

Those in sustained remission were then randomized double blind to one of three groups: an additional 48 weeks of certolizumab pegol at the full maintenance dose of 200 mg every 2 weeks, reduced maintenance dosing at 200 mg every 4 weeks, or placebo. During this period, 83.7% of the group who continued on full-dose certolizumab remained flare free, as did 79% of those on the reduced maintenance dose. In contrast, only 20.2% of patients in whom the biologic was completely withdrawn remained flare free. The investigators concluded that certolizumab dose reduction is a winning strategy for maintenance of clinical remission, as it reduces costs and limits long-term exposure to immunosuppressive therapy while maintaining clinical benefits.
 

All biologics aren’t equal when it comes to anterior uveitis risk

An analysis of Swedish Rheumatology Quality Register data presented at the 2020 EULAR meeting concluded that, among 3,568 patients started on one of four biologics for treatment of spondyloarthritis, the incidence of anterior uveitis was 2.9 per 100 patient-years in those on infliximab (Remicade), 4.0 per 100 patient-years with adalimumab (Humira), 6.8 per 100 patient-years with secukinumab (Cosentyx), and 7.5 per 100 patient-years with etanercept (Enbrel).

Bruce Jancin/MDedge News

“This is important information for us in the clinic. The big question has been, do we see a reduced risk of anterior uveitis with secukinumab, an interleukin-17 inhibitor,” observed RWCS director Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.

“When I’ve switched people with uveitis to secukinumab or ixekizumab [Taltz], I do see it come back. So I think it’s important to have these data out there,” Dr. Ogdie said.

Certolizumab pegol markedly reduced the incidence of anterior uveitis flares in patients with radiographic and nonradiographic axSpA and a history of recurrent uveitis flares in the ongoing phase 4 C-VIEW study. In the 48 weeks prior to going on certolizumab pegol, the 89 participants included in this analysis had an acute anterior uveitis incidence of 1.5 episodes per patient; during their first 48 weeks on the TNF inhibitor, the rate plunged to 0.2 episodes, representing an 87% reduction.
 

Secukinumab ‘not the obvious choice’ after inadequate response to a TNF inhibitor

While it might seem logical to turn to an IL-17 inhibitor in patients with an inadequate response to one or more TNF inhibitors, two recently published studies suggest that starting secukinumab is not more effective than trying yet another TNF inhibitor.

A retrospective analysis of Swiss registry data on next-step therapy in 390 axSpA patients who had withdrawn from one or more TNF inhibitors concluded that efficacy at 1 year in the 106 who switched to secukinumab wasn’t significantly different than in the 284 who moved on to another TNF inhibitor.

Similarly, an analysis of 10,583 courses of biologic therapy in 8,050 axSpA patients in five Nordic registries concluded that secukinumab and adalimumab as second-line therapy in patients with inadequate response to an initial TNF inhibitor performed similarly through 1 year of follow-up. However, in patients who’d previously failed to respond to two or three different biologic agents, adalimumab proved superior to the interleukin-17 inhibitor.

“These are two studies that don’t support the intuitive notion of trying a drug with a different mechanism of action when a patient has an inadequate response to a TNF inhibitor. It’s not clear that’s going to make a difference. It doesn’t mean secukinumab can’t work, but it means secukinumab is not the obvious choice,” Dr. Ruderman commented.

All three speakers reported financial relationships with numerous pharmaceutical companies.

bjancin@mdedge.com

Rheumatologists can look forward to the likely regulatory approval of the oral Janus kinase inhibitors tofacitinib and upadacitinib for the treatment of axial spondyloarthritis in the first half of 2021, speakers predicted at the 2021 Rheumatology Winter Clinical Symposium.

This will be a major advance in the treatment of axial spondyloarthritis (axSpA) and promises to be one of the overall highlights of the coming year in rheumatology, according to the speakers. Both medications are now under Food and Drug Administration review for the proposed new indication.

“My sense is within the next 6 months we’re going to have two different oral JAK inhibitors that offer a new option for our ankylosing spondylitis and axial spondyloarthritis patients,” predicted Eric M. Ruderman, MD, professor of medicine (rheumatology) at Northwestern University, Chicago.

Alexis R. Ogdie, MD, MSCE, noted that, at present, only two classes of potent medications are available for treatment of axial spondyloarthritis: tumor necrosis factor (TNF) inhibitors and anti–interleukin-17 biologics.

“I think it would be so exciting to have more treatment options. To have only two classes of drugs you can use for this disease is not enough,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.

She and her fellow panelists also highlighted other recent key developments in axSpA, including epidemiologic evidence that case numbers are climbing sharply, identification of two previously unrecognized common comorbidities, a successful biologic remission induction and maintenance dose–reduction strategy, data on the best and worst biologics for patients with anterior uveitis, and evidence regarding next-step therapy in axSpA patients who’ve had an inadequate response to a TNF inhibitor.
 

The JAK inhibitors are coming

Oral tofacitinib (Xeljanz) at 5 mg twice daily was the focus of a pivotal phase 3, double-blind, 16-week, placebo-controlled clinical trial including 269 patients with axSpA. The results were presented at the 2020 annual meeting of the American College of Rheumatology. The primary endpoint was at least a 20% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 20). This was accomplished in 56.4% of patients on tofacitinib and 29.4% of placebo-treated controls. The ASAS 40 response rate was even more impressive: 40.6% with the JAK inhibitor, compared with 12.5% with placebo. There was one serious infection in the tofacitinib group, but no cases of venous thromboembolism, interstitial lung disease, opportunistic infection, major adverse cardiovascular events, or malignancy in this brief 4-month study.

Also now under FDA review are data from SELECT-AXIS 1, a phase 2/3, double-blind trial in which 187 biologic-naive patients with ankylosing spondylitis were randomized to 14 weeks of upadacitinib (Rinvoq) at 15 mg once daily or placebo. The primary endpoint, an ASAS 40 response, occurred in 51.6% of patients on the JAK inhibitor and half as many controls.

“They saw improvement in MRI scores with upadacitinib, so there’s biologic plausibility to this,” Dr. Ruderman noted.

He predicted the JAK inhibitors are going to have a big impact in clinical practice, especially in men.

“I have a lot of ankylosing spondylitis and axial spondyloarthritis patients on NSAIDs who I’m not convinced are doing as well as they could, but they push back every time I raise the possibility of going on a biologic,” the rheumatologist said. “I suspect that, given the rapid response with JAK inhibitors here, as in rheumatoid arthritis, it might be a little bit easier to persuade these people to give this a try for 4-6 weeks and then see how much better they are. It’s a pill. You don’t have to give yourself a shot.”

Dr. Ogdie predicted the new oral agents will bring more axSpA patients into rheumatologists’ offices.

“I think it’ll be kind of like the apremilast effect in psoriasis, where the drug got a lot more people into the market,” she said.

U.S. ankylosing spondylitis prevalence rising

The diagnostic prevalence of axSpA in the United States increased by 86% between 2006 and 2014 in a retrospective analysis based on Medicare fee-for-service claims data. A separate analysis using IBM MarketScan data for the same years was confirmatory, showing a 56% increase, Jeffrey R. Curtis, MD, MS, MPH, of the University of Alabama at Birmingham reported at the 2020 annual meeting of the European League Against Rheumatism (EULAR), now known as the European Alliance of Associations for Rheumatology.

“I think the take home is we’re seeing more of this. Some of this is likely due to increased awareness and inclusion of nonradiographic disease,” according to Dr. Ruderman.
 

Two previously overlooked comorbidities

It’s well recognized that 5%-10% of patients with axSpA have concurrent inflammatory bowel disease. But how about irritable bowel syndrome (IBS)?

A study of 186 Swedish patients with axSpA in the population-based SPARTAKUS registry, none with inflammatory bowel disease, concluded that 30% of them met ROME III diagnostic criteria for IBS, compared with 16% of healthy controls. Of note, the axSpA patients with comorbid IBS had significantly worse axSpA disease outcomes, compared with those without IBS as measured by pain, fatigue, and quality-of-life scores, as well as significantly greater disease activity on the Bath Ankylosing Spondylitis Disease Activity Index.

New-onset inflammatory back pain occurred in a hefty 24% of 513 Saudi patients placed on isotretinoin for acne. About 42% of those with inflammatory back pain displayed evidence of sacroiliitis on MRI. Moreover, 52% of patients with MRI-proven sacroiliitis fulfilled ASAS criteria for axSpA. In this longitudinal study, the MRI abnormalities and back pain symptoms completely resolved after isotretinoin discontinuation, but it took a long time: up to 9 months.

“When you see these people with inflammatory back pain on isotretinoin, I think it’s important that before you saddle them with a diagnosis that they have axSpA – a diagnosis that will go with them forever – give them time off drug, because this can look like the real thing. It’s something to think about as these pretty young kids come in to see you with back pain: Always ask about their medication history because it could be important,” Dr. Ruderman said.

A successful biologic remission induction-and-maintenance strategy

The phase 3b, multicenter C-OPTIMISE study sought to determine the best strategy for avoiding axSpA flares once sustained clinical remission has been achieved with a TNF inhibitor, in this case certolizumab pegol (Cimzia). The first part of the trial involved 736 patients with early axSpA, including 329 with nonradiographic disease. During the 48-week open-label induction period, 43.9% of patients achieved sustained clinical remission at the approved dose of 200 mg every 2 weeks, with similar success rates in radiographic and nonradiographic axSpA.

Those in sustained remission were then randomized double blind to one of three groups: an additional 48 weeks of certolizumab pegol at the full maintenance dose of 200 mg every 2 weeks, reduced maintenance dosing at 200 mg every 4 weeks, or placebo. During this period, 83.7% of the group who continued on full-dose certolizumab remained flare free, as did 79% of those on the reduced maintenance dose. In contrast, only 20.2% of patients in whom the biologic was completely withdrawn remained flare free. The investigators concluded that certolizumab dose reduction is a winning strategy for maintenance of clinical remission, as it reduces costs and limits long-term exposure to immunosuppressive therapy while maintaining clinical benefits.
 

All biologics aren’t equal when it comes to anterior uveitis risk

An analysis of Swedish Rheumatology Quality Register data presented at the 2020 EULAR meeting concluded that, among 3,568 patients started on one of four biologics for treatment of spondyloarthritis, the incidence of anterior uveitis was 2.9 per 100 patient-years in those on infliximab (Remicade), 4.0 per 100 patient-years with adalimumab (Humira), 6.8 per 100 patient-years with secukinumab (Cosentyx), and 7.5 per 100 patient-years with etanercept (Enbrel).

Bruce Jancin/MDedge News

“This is important information for us in the clinic. The big question has been, do we see a reduced risk of anterior uveitis with secukinumab, an interleukin-17 inhibitor,” observed RWCS director Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.

“When I’ve switched people with uveitis to secukinumab or ixekizumab [Taltz], I do see it come back. So I think it’s important to have these data out there,” Dr. Ogdie said.

Certolizumab pegol markedly reduced the incidence of anterior uveitis flares in patients with radiographic and nonradiographic axSpA and a history of recurrent uveitis flares in the ongoing phase 4 C-VIEW study. In the 48 weeks prior to going on certolizumab pegol, the 89 participants included in this analysis had an acute anterior uveitis incidence of 1.5 episodes per patient; during their first 48 weeks on the TNF inhibitor, the rate plunged to 0.2 episodes, representing an 87% reduction.
 

Secukinumab ‘not the obvious choice’ after inadequate response to a TNF inhibitor

While it might seem logical to turn to an IL-17 inhibitor in patients with an inadequate response to one or more TNF inhibitors, two recently published studies suggest that starting secukinumab is not more effective than trying yet another TNF inhibitor.

A retrospective analysis of Swiss registry data on next-step therapy in 390 axSpA patients who had withdrawn from one or more TNF inhibitors concluded that efficacy at 1 year in the 106 who switched to secukinumab wasn’t significantly different than in the 284 who moved on to another TNF inhibitor.

Similarly, an analysis of 10,583 courses of biologic therapy in 8,050 axSpA patients in five Nordic registries concluded that secukinumab and adalimumab as second-line therapy in patients with inadequate response to an initial TNF inhibitor performed similarly through 1 year of follow-up. However, in patients who’d previously failed to respond to two or three different biologic agents, adalimumab proved superior to the interleukin-17 inhibitor.

“These are two studies that don’t support the intuitive notion of trying a drug with a different mechanism of action when a patient has an inadequate response to a TNF inhibitor. It’s not clear that’s going to make a difference. It doesn’t mean secukinumab can’t work, but it means secukinumab is not the obvious choice,” Dr. Ruderman commented.

All three speakers reported financial relationships with numerous pharmaceutical companies.

bjancin@mdedge.com

Rheumatologists can look forward to the likely regulatory approval of the oral Janus kinase inhibitors tofacitinib and upadacitinib for the treatment of axial spondyloarthritis in the first half of 2021, speakers predicted at the 2021 Rheumatology Winter Clinical Symposium.

This will be a major advance in the treatment of axial spondyloarthritis (axSpA) and promises to be one of the overall highlights of the coming year in rheumatology, according to the speakers. Both medications are now under Food and Drug Administration review for the proposed new indication.

“My sense is within the next 6 months we’re going to have two different oral JAK inhibitors that offer a new option for our ankylosing spondylitis and axial spondyloarthritis patients,” predicted Eric M. Ruderman, MD, professor of medicine (rheumatology) at Northwestern University, Chicago.

Alexis R. Ogdie, MD, MSCE, noted that, at present, only two classes of potent medications are available for treatment of axial spondyloarthritis: tumor necrosis factor (TNF) inhibitors and anti–interleukin-17 biologics.

“I think it would be so exciting to have more treatment options. To have only two classes of drugs you can use for this disease is not enough,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.

She and her fellow panelists also highlighted other recent key developments in axSpA, including epidemiologic evidence that case numbers are climbing sharply, identification of two previously unrecognized common comorbidities, a successful biologic remission induction and maintenance dose–reduction strategy, data on the best and worst biologics for patients with anterior uveitis, and evidence regarding next-step therapy in axSpA patients who’ve had an inadequate response to a TNF inhibitor.
 

The JAK inhibitors are coming

Oral tofacitinib (Xeljanz) at 5 mg twice daily was the focus of a pivotal phase 3, double-blind, 16-week, placebo-controlled clinical trial including 269 patients with axSpA. The results were presented at the 2020 annual meeting of the American College of Rheumatology. The primary endpoint was at least a 20% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 20). This was accomplished in 56.4% of patients on tofacitinib and 29.4% of placebo-treated controls. The ASAS 40 response rate was even more impressive: 40.6% with the JAK inhibitor, compared with 12.5% with placebo. There was one serious infection in the tofacitinib group, but no cases of venous thromboembolism, interstitial lung disease, opportunistic infection, major adverse cardiovascular events, or malignancy in this brief 4-month study.

Also now under FDA review are data from SELECT-AXIS 1, a phase 2/3, double-blind trial in which 187 biologic-naive patients with ankylosing spondylitis were randomized to 14 weeks of upadacitinib (Rinvoq) at 15 mg once daily or placebo. The primary endpoint, an ASAS 40 response, occurred in 51.6% of patients on the JAK inhibitor and half as many controls.

“They saw improvement in MRI scores with upadacitinib, so there’s biologic plausibility to this,” Dr. Ruderman noted.

He predicted the JAK inhibitors are going to have a big impact in clinical practice, especially in men.

“I have a lot of ankylosing spondylitis and axial spondyloarthritis patients on NSAIDs who I’m not convinced are doing as well as they could, but they push back every time I raise the possibility of going on a biologic,” the rheumatologist said. “I suspect that, given the rapid response with JAK inhibitors here, as in rheumatoid arthritis, it might be a little bit easier to persuade these people to give this a try for 4-6 weeks and then see how much better they are. It’s a pill. You don’t have to give yourself a shot.”

Dr. Ogdie predicted the new oral agents will bring more axSpA patients into rheumatologists’ offices.

“I think it’ll be kind of like the apremilast effect in psoriasis, where the drug got a lot more people into the market,” she said.

U.S. ankylosing spondylitis prevalence rising

The diagnostic prevalence of axSpA in the United States increased by 86% between 2006 and 2014 in a retrospective analysis based on Medicare fee-for-service claims data. A separate analysis using IBM MarketScan data for the same years was confirmatory, showing a 56% increase, Jeffrey R. Curtis, MD, MS, MPH, of the University of Alabama at Birmingham reported at the 2020 annual meeting of the European League Against Rheumatism (EULAR), now known as the European Alliance of Associations for Rheumatology.

“I think the take home is we’re seeing more of this. Some of this is likely due to increased awareness and inclusion of nonradiographic disease,” according to Dr. Ruderman.
 

Two previously overlooked comorbidities

It’s well recognized that 5%-10% of patients with axSpA have concurrent inflammatory bowel disease. But how about irritable bowel syndrome (IBS)?

A study of 186 Swedish patients with axSpA in the population-based SPARTAKUS registry, none with inflammatory bowel disease, concluded that 30% of them met ROME III diagnostic criteria for IBS, compared with 16% of healthy controls. Of note, the axSpA patients with comorbid IBS had significantly worse axSpA disease outcomes, compared with those without IBS as measured by pain, fatigue, and quality-of-life scores, as well as significantly greater disease activity on the Bath Ankylosing Spondylitis Disease Activity Index.

New-onset inflammatory back pain occurred in a hefty 24% of 513 Saudi patients placed on isotretinoin for acne. About 42% of those with inflammatory back pain displayed evidence of sacroiliitis on MRI. Moreover, 52% of patients with MRI-proven sacroiliitis fulfilled ASAS criteria for axSpA. In this longitudinal study, the MRI abnormalities and back pain symptoms completely resolved after isotretinoin discontinuation, but it took a long time: up to 9 months.

“When you see these people with inflammatory back pain on isotretinoin, I think it’s important that before you saddle them with a diagnosis that they have axSpA – a diagnosis that will go with them forever – give them time off drug, because this can look like the real thing. It’s something to think about as these pretty young kids come in to see you with back pain: Always ask about their medication history because it could be important,” Dr. Ruderman said.

A successful biologic remission induction-and-maintenance strategy

The phase 3b, multicenter C-OPTIMISE study sought to determine the best strategy for avoiding axSpA flares once sustained clinical remission has been achieved with a TNF inhibitor, in this case certolizumab pegol (Cimzia). The first part of the trial involved 736 patients with early axSpA, including 329 with nonradiographic disease. During the 48-week open-label induction period, 43.9% of patients achieved sustained clinical remission at the approved dose of 200 mg every 2 weeks, with similar success rates in radiographic and nonradiographic axSpA.

Those in sustained remission were then randomized double blind to one of three groups: an additional 48 weeks of certolizumab pegol at the full maintenance dose of 200 mg every 2 weeks, reduced maintenance dosing at 200 mg every 4 weeks, or placebo. During this period, 83.7% of the group who continued on full-dose certolizumab remained flare free, as did 79% of those on the reduced maintenance dose. In contrast, only 20.2% of patients in whom the biologic was completely withdrawn remained flare free. The investigators concluded that certolizumab dose reduction is a winning strategy for maintenance of clinical remission, as it reduces costs and limits long-term exposure to immunosuppressive therapy while maintaining clinical benefits.
 

All biologics aren’t equal when it comes to anterior uveitis risk

An analysis of Swedish Rheumatology Quality Register data presented at the 2020 EULAR meeting concluded that, among 3,568 patients started on one of four biologics for treatment of spondyloarthritis, the incidence of anterior uveitis was 2.9 per 100 patient-years in those on infliximab (Remicade), 4.0 per 100 patient-years with adalimumab (Humira), 6.8 per 100 patient-years with secukinumab (Cosentyx), and 7.5 per 100 patient-years with etanercept (Enbrel).

Bruce Jancin/MDedge News

“This is important information for us in the clinic. The big question has been, do we see a reduced risk of anterior uveitis with secukinumab, an interleukin-17 inhibitor,” observed RWCS director Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.

“When I’ve switched people with uveitis to secukinumab or ixekizumab [Taltz], I do see it come back. So I think it’s important to have these data out there,” Dr. Ogdie said.

Certolizumab pegol markedly reduced the incidence of anterior uveitis flares in patients with radiographic and nonradiographic axSpA and a history of recurrent uveitis flares in the ongoing phase 4 C-VIEW study. In the 48 weeks prior to going on certolizumab pegol, the 89 participants included in this analysis had an acute anterior uveitis incidence of 1.5 episodes per patient; during their first 48 weeks on the TNF inhibitor, the rate plunged to 0.2 episodes, representing an 87% reduction.
 

Secukinumab ‘not the obvious choice’ after inadequate response to a TNF inhibitor

While it might seem logical to turn to an IL-17 inhibitor in patients with an inadequate response to one or more TNF inhibitors, two recently published studies suggest that starting secukinumab is not more effective than trying yet another TNF inhibitor.

A retrospective analysis of Swiss registry data on next-step therapy in 390 axSpA patients who had withdrawn from one or more TNF inhibitors concluded that efficacy at 1 year in the 106 who switched to secukinumab wasn’t significantly different than in the 284 who moved on to another TNF inhibitor.

Similarly, an analysis of 10,583 courses of biologic therapy in 8,050 axSpA patients in five Nordic registries concluded that secukinumab and adalimumab as second-line therapy in patients with inadequate response to an initial TNF inhibitor performed similarly through 1 year of follow-up. However, in patients who’d previously failed to respond to two or three different biologic agents, adalimumab proved superior to the interleukin-17 inhibitor.

“These are two studies that don’t support the intuitive notion of trying a drug with a different mechanism of action when a patient has an inadequate response to a TNF inhibitor. It’s not clear that’s going to make a difference. It doesn’t mean secukinumab can’t work, but it means secukinumab is not the obvious choice,” Dr. Ruderman commented.

All three speakers reported financial relationships with numerous pharmaceutical companies.

bjancin@mdedge.com

No Food and Drug Administration–approved treatment currently exists for molluscum contagiosum, which affects an estimated 6 million people in the United States, but that could soon change, according to Leon H. Kircik, MD.

“The treatment of molluscum is still an unmet need,” Dr. Kircik, clinical professor of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said at the Orlando Dermatology Aesthetic and Clinical Conference. However, a proprietary drug-device combination of cantharidin 0.7% administered through a single-use precision applicator, which has been tested in phase 3 studies, is currently under FDA review. The manufacturer, Verrica Pharmaceuticals resubmitted a new drug application for the product, VP-102, in December 2020.

“VP-102 features a visualization agent so the injector can see which lesions have been treated, as well as a bittering agent to mitigate oral ingestion by children. Complete clearance at 12 weeks ranged from 46% to 54% of patients, while lesion count reduction compared with baseline ranged from 69% to 82%.”
 

Acne

In August, 2020, clascoterone 1% cream was approved for the treatment of acne in patients 12 years and older, a development that Dr. Kircik said “can be a game changer in acne treatment.” Clascoterone cream 1% exhibits strong, selective anti-androgen activity by targeting androgen receptors in the skin, not systemically. “It limits or blocks transcription of androgen responsive genes, but it also has an anti-inflammatory effect and an anti-sebum effect,” he explained.

According to results from two phase 3 trials of the product, a response of clear or almost clear on the IGA scale at week 12 was achieved in 18.4% of those on treatment vs. 9% of those on vehicle in one study (P less than .001) and 20.3% vs. 6.5%, respectively, in the second study (P less than .001). Clascoterone is also being evaluated for treating androgenetic alopecia.

In Dr. Kircik’s clinical experience, retinoids can be helpful for patients with moderate to severe acne. “We always use them for anticomedogenic effects, but we also know that they have anti-inflammatory effects,” he said. “They actually inhibit toll-like receptor activity. They also inhibit the AP-1 pathway by causing a reduction in inflammatory signaling associated with collagen degradation and scarring.”

The most recent retinoid to be approved for the topical treatment of acne was 0.005% trifarotene cream, in 2019, for patients aged 9 years and older. “But when we got the results, it was not that exciting,” a difference of about 3.6 (mean) inflammatory lesion reduction between the active and the vehicle arm, said Dr. Kircik, medical director of Physicians Skin Care in Louisville, Ky. “According to the package insert, treatment side effects included mild to moderate erythema in 59% of patients, scaling in 65%, dryness in 69%, and stinging/burning in 56%, which makes it difficult to use in our clinical practice.”

The drug was also tested for treating truncal acne. However, one comparative study showed that tazarotene 0.045% lotion spread an average of 36.7 square centimeters farther than the trifarotene cream, which makes the tazarotene lotion easier to use on the chest and back, he said.

Dr. Kircik also discussed 4% minocycline, a hydrophobic, topical foam formulation of minocycline that was approved by the FDA in 2019 for the treatment of moderate to severe acne, for patients aged 9 and older. In a 12-week study that involved 1,488 patients (mean age was about 20 years), investigators observed a 56% reduction in inflammatory lesion count among those treated with minocycline 4%, compared with 43% in the vehicle group.

Dr. Kircik, one of the authors of the study, noted that the hydrophobic composition of minocycline 4% allows for stable and efficient delivery of an inherently unstable active pharmaceutical ingredient such as minocycline. “It’s free of primary irritants such as surfactants and short chain alcohols, which makes it much more tolerable,” he said. “The unique physical foam characteristics facilitate ease of application and absorption at target sites.”

Dr. Kircik reported that he serves as a consultant and/or adviser to numerous pharmaceutical companies, including Galderma, the manufacturer of trifarotene cream.

dbrunk@mdedge.com

No Food and Drug Administration–approved treatment currently exists for molluscum contagiosum, which affects an estimated 6 million people in the United States, but that could soon change, according to Leon H. Kircik, MD.

“The treatment of molluscum is still an unmet need,” Dr. Kircik, clinical professor of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said at the Orlando Dermatology Aesthetic and Clinical Conference. However, a proprietary drug-device combination of cantharidin 0.7% administered through a single-use precision applicator, which has been tested in phase 3 studies, is currently under FDA review. The manufacturer, Verrica Pharmaceuticals resubmitted a new drug application for the product, VP-102, in December 2020.

“VP-102 features a visualization agent so the injector can see which lesions have been treated, as well as a bittering agent to mitigate oral ingestion by children. Complete clearance at 12 weeks ranged from 46% to 54% of patients, while lesion count reduction compared with baseline ranged from 69% to 82%.”
 

Acne

In August, 2020, clascoterone 1% cream was approved for the treatment of acne in patients 12 years and older, a development that Dr. Kircik said “can be a game changer in acne treatment.” Clascoterone cream 1% exhibits strong, selective anti-androgen activity by targeting androgen receptors in the skin, not systemically. “It limits or blocks transcription of androgen responsive genes, but it also has an anti-inflammatory effect and an anti-sebum effect,” he explained.

According to results from two phase 3 trials of the product, a response of clear or almost clear on the IGA scale at week 12 was achieved in 18.4% of those on treatment vs. 9% of those on vehicle in one study (P less than .001) and 20.3% vs. 6.5%, respectively, in the second study (P less than .001). Clascoterone is also being evaluated for treating androgenetic alopecia.

In Dr. Kircik’s clinical experience, retinoids can be helpful for patients with moderate to severe acne. “We always use them for anticomedogenic effects, but we also know that they have anti-inflammatory effects,” he said. “They actually inhibit toll-like receptor activity. They also inhibit the AP-1 pathway by causing a reduction in inflammatory signaling associated with collagen degradation and scarring.”

The most recent retinoid to be approved for the topical treatment of acne was 0.005% trifarotene cream, in 2019, for patients aged 9 years and older. “But when we got the results, it was not that exciting,” a difference of about 3.6 (mean) inflammatory lesion reduction between the active and the vehicle arm, said Dr. Kircik, medical director of Physicians Skin Care in Louisville, Ky. “According to the package insert, treatment side effects included mild to moderate erythema in 59% of patients, scaling in 65%, dryness in 69%, and stinging/burning in 56%, which makes it difficult to use in our clinical practice.”

The drug was also tested for treating truncal acne. However, one comparative study showed that tazarotene 0.045% lotion spread an average of 36.7 square centimeters farther than the trifarotene cream, which makes the tazarotene lotion easier to use on the chest and back, he said.

Dr. Kircik also discussed 4% minocycline, a hydrophobic, topical foam formulation of minocycline that was approved by the FDA in 2019 for the treatment of moderate to severe acne, for patients aged 9 and older. In a 12-week study that involved 1,488 patients (mean age was about 20 years), investigators observed a 56% reduction in inflammatory lesion count among those treated with minocycline 4%, compared with 43% in the vehicle group.

Dr. Kircik, one of the authors of the study, noted that the hydrophobic composition of minocycline 4% allows for stable and efficient delivery of an inherently unstable active pharmaceutical ingredient such as minocycline. “It’s free of primary irritants such as surfactants and short chain alcohols, which makes it much more tolerable,” he said. “The unique physical foam characteristics facilitate ease of application and absorption at target sites.”

Dr. Kircik reported that he serves as a consultant and/or adviser to numerous pharmaceutical companies, including Galderma, the manufacturer of trifarotene cream.

dbrunk@mdedge.com

No Food and Drug Administration–approved treatment currently exists for molluscum contagiosum, which affects an estimated 6 million people in the United States, but that could soon change, according to Leon H. Kircik, MD.

“The treatment of molluscum is still an unmet need,” Dr. Kircik, clinical professor of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said at the Orlando Dermatology Aesthetic and Clinical Conference. However, a proprietary drug-device combination of cantharidin 0.7% administered through a single-use precision applicator, which has been tested in phase 3 studies, is currently under FDA review. The manufacturer, Verrica Pharmaceuticals resubmitted a new drug application for the product, VP-102, in December 2020.

“VP-102 features a visualization agent so the injector can see which lesions have been treated, as well as a bittering agent to mitigate oral ingestion by children. Complete clearance at 12 weeks ranged from 46% to 54% of patients, while lesion count reduction compared with baseline ranged from 69% to 82%.”
 

Acne

In August, 2020, clascoterone 1% cream was approved for the treatment of acne in patients 12 years and older, a development that Dr. Kircik said “can be a game changer in acne treatment.” Clascoterone cream 1% exhibits strong, selective anti-androgen activity by targeting androgen receptors in the skin, not systemically. “It limits or blocks transcription of androgen responsive genes, but it also has an anti-inflammatory effect and an anti-sebum effect,” he explained.

According to results from two phase 3 trials of the product, a response of clear or almost clear on the IGA scale at week 12 was achieved in 18.4% of those on treatment vs. 9% of those on vehicle in one study (P less than .001) and 20.3% vs. 6.5%, respectively, in the second study (P less than .001). Clascoterone is also being evaluated for treating androgenetic alopecia.

In Dr. Kircik’s clinical experience, retinoids can be helpful for patients with moderate to severe acne. “We always use them for anticomedogenic effects, but we also know that they have anti-inflammatory effects,” he said. “They actually inhibit toll-like receptor activity. They also inhibit the AP-1 pathway by causing a reduction in inflammatory signaling associated with collagen degradation and scarring.”

The most recent retinoid to be approved for the topical treatment of acne was 0.005% trifarotene cream, in 2019, for patients aged 9 years and older. “But when we got the results, it was not that exciting,” a difference of about 3.6 (mean) inflammatory lesion reduction between the active and the vehicle arm, said Dr. Kircik, medical director of Physicians Skin Care in Louisville, Ky. “According to the package insert, treatment side effects included mild to moderate erythema in 59% of patients, scaling in 65%, dryness in 69%, and stinging/burning in 56%, which makes it difficult to use in our clinical practice.”

The drug was also tested for treating truncal acne. However, one comparative study showed that tazarotene 0.045% lotion spread an average of 36.7 square centimeters farther than the trifarotene cream, which makes the tazarotene lotion easier to use on the chest and back, he said.

Dr. Kircik also discussed 4% minocycline, a hydrophobic, topical foam formulation of minocycline that was approved by the FDA in 2019 for the treatment of moderate to severe acne, for patients aged 9 and older. In a 12-week study that involved 1,488 patients (mean age was about 20 years), investigators observed a 56% reduction in inflammatory lesion count among those treated with minocycline 4%, compared with 43% in the vehicle group.

Dr. Kircik, one of the authors of the study, noted that the hydrophobic composition of minocycline 4% allows for stable and efficient delivery of an inherently unstable active pharmaceutical ingredient such as minocycline. “It’s free of primary irritants such as surfactants and short chain alcohols, which makes it much more tolerable,” he said. “The unique physical foam characteristics facilitate ease of application and absorption at target sites.”

Dr. Kircik reported that he serves as a consultant and/or adviser to numerous pharmaceutical companies, including Galderma, the manufacturer of trifarotene cream.

dbrunk@mdedge.com

Many dermatologists favor using either needles or cannulas for dermal filler treatments, but there’s a role for both instruments, according to Terrence Keaney, MD.

FlamingoImages/iStock/Getty Images

“You may be a needle person or a cannula person, but it doesn’t have to be that way,” he said during the Orlando Dermatology Aesthetic and Clinical Conference. “There are pros and cons of both techniques, but I think there’s a place for both.”

Such emerging data present a conundrum, though. If someone is comfortable injecting dermal filler with needles, why switch to using cannulas? After all, a case study reported arterial penetration with blunt-tipped cannulas using injectables . “Cannulas are not 100% safe,” Dr. Keaney said. “One of my mentors once said, “If a vascular event has not happened to you yet, you have not injected enough. These things can happen even in the most experienced hands, whether you use a needle or a cannula.”

However, safety data from a recently published retrospective study demonstrated that cannulas are less likely to be associated with occlusions compared with needles (a risk of 1 occlusion per 40,882 injections vs. 1 occlusion per 6,410 injections (P less than .001) (JAMA Dermatol. 2021 Feb 1;157[2]:174-80).

“Cannulas are generally safer because the blunt tip kind of dissects tissue and pushes vessels away,” he said. “That doesn’t mean it can’t get into a vessel, it just requires greater force to penetrate facial arteries with a cannula. Finer tips may be easier to use.”

Larger cannulas can tear into an arterial wall when the artery wall is relatively fixed, so it cannot slide aside enough to avoid injury, Dr. Keaney continued. “Arterial location perpendicular to cannula trajectory carries the most risk,” he said. Meanwhile, filler-induced blindness, which he characterized as “the worst possible outcome,” is often due to the retrograde embolization of the product. This can occur with injection pressures greater than the sum of the systolic arterial pressure and the frictional forces due to viscous flow.

Dr. Keaney said he uses both needles and cannulas in his clinical practice. “I use a needle to inject on bone if I want to mimic bony projections along the zygomatic arch or jawline or chin,” he said. “I think a needle can get those boluses to develop that projection that you want. If I’m injecting within soft tissue plane, I use a 22 G cannula and keep the cannula moving within the tissue. I inject slowly and less than 0.2 cc per bolus. I compress when injecting on the nose and I’m cautious to inject previous patients who have undergone plastic surgery or in areas of previous scarring.”

Dr. Keaney reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies.

dbrunk@mdedge.com

Many dermatologists favor using either needles or cannulas for dermal filler treatments, but there’s a role for both instruments, according to Terrence Keaney, MD.

FlamingoImages/iStock/Getty Images

“You may be a needle person or a cannula person, but it doesn’t have to be that way,” he said during the Orlando Dermatology Aesthetic and Clinical Conference. “There are pros and cons of both techniques, but I think there’s a place for both.”

Such emerging data present a conundrum, though. If someone is comfortable injecting dermal filler with needles, why switch to using cannulas? After all, a case study reported arterial penetration with blunt-tipped cannulas using injectables . “Cannulas are not 100% safe,” Dr. Keaney said. “One of my mentors once said, “If a vascular event has not happened to you yet, you have not injected enough. These things can happen even in the most experienced hands, whether you use a needle or a cannula.”

However, safety data from a recently published retrospective study demonstrated that cannulas are less likely to be associated with occlusions compared with needles (a risk of 1 occlusion per 40,882 injections vs. 1 occlusion per 6,410 injections (P less than .001) (JAMA Dermatol. 2021 Feb 1;157[2]:174-80).

“Cannulas are generally safer because the blunt tip kind of dissects tissue and pushes vessels away,” he said. “That doesn’t mean it can’t get into a vessel, it just requires greater force to penetrate facial arteries with a cannula. Finer tips may be easier to use.”

Larger cannulas can tear into an arterial wall when the artery wall is relatively fixed, so it cannot slide aside enough to avoid injury, Dr. Keaney continued. “Arterial location perpendicular to cannula trajectory carries the most risk,” he said. Meanwhile, filler-induced blindness, which he characterized as “the worst possible outcome,” is often due to the retrograde embolization of the product. This can occur with injection pressures greater than the sum of the systolic arterial pressure and the frictional forces due to viscous flow.

Dr. Keaney said he uses both needles and cannulas in his clinical practice. “I use a needle to inject on bone if I want to mimic bony projections along the zygomatic arch or jawline or chin,” he said. “I think a needle can get those boluses to develop that projection that you want. If I’m injecting within soft tissue plane, I use a 22 G cannula and keep the cannula moving within the tissue. I inject slowly and less than 0.2 cc per bolus. I compress when injecting on the nose and I’m cautious to inject previous patients who have undergone plastic surgery or in areas of previous scarring.”

Dr. Keaney reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies.

dbrunk@mdedge.com

Many dermatologists favor using either needles or cannulas for dermal filler treatments, but there’s a role for both instruments, according to Terrence Keaney, MD.

FlamingoImages/iStock/Getty Images

“You may be a needle person or a cannula person, but it doesn’t have to be that way,” he said during the Orlando Dermatology Aesthetic and Clinical Conference. “There are pros and cons of both techniques, but I think there’s a place for both.”

Such emerging data present a conundrum, though. If someone is comfortable injecting dermal filler with needles, why switch to using cannulas? After all, a case study reported arterial penetration with blunt-tipped cannulas using injectables . “Cannulas are not 100% safe,” Dr. Keaney said. “One of my mentors once said, “If a vascular event has not happened to you yet, you have not injected enough. These things can happen even in the most experienced hands, whether you use a needle or a cannula.”

However, safety data from a recently published retrospective study demonstrated that cannulas are less likely to be associated with occlusions compared with needles (a risk of 1 occlusion per 40,882 injections vs. 1 occlusion per 6,410 injections (P less than .001) (JAMA Dermatol. 2021 Feb 1;157[2]:174-80).

“Cannulas are generally safer because the blunt tip kind of dissects tissue and pushes vessels away,” he said. “That doesn’t mean it can’t get into a vessel, it just requires greater force to penetrate facial arteries with a cannula. Finer tips may be easier to use.”

Larger cannulas can tear into an arterial wall when the artery wall is relatively fixed, so it cannot slide aside enough to avoid injury, Dr. Keaney continued. “Arterial location perpendicular to cannula trajectory carries the most risk,” he said. Meanwhile, filler-induced blindness, which he characterized as “the worst possible outcome,” is often due to the retrograde embolization of the product. This can occur with injection pressures greater than the sum of the systolic arterial pressure and the frictional forces due to viscous flow.

Dr. Keaney said he uses both needles and cannulas in his clinical practice. “I use a needle to inject on bone if I want to mimic bony projections along the zygomatic arch or jawline or chin,” he said. “I think a needle can get those boluses to develop that projection that you want. If I’m injecting within soft tissue plane, I use a 22 G cannula and keep the cannula moving within the tissue. I inject slowly and less than 0.2 cc per bolus. I compress when injecting on the nose and I’m cautious to inject previous patients who have undergone plastic surgery or in areas of previous scarring.”

Dr. Keaney reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies.

dbrunk@mdedge.com

For many adults, depression and chronic medical conditions are inextricably linked.

In fact, the prevalence of depression is 2-10 times higher among people with chronic medical conditions, particularly in people with chronic pain, where the prevalence reaches 40%-60%, according to Jonathan E. Alpert, MD, PhD.

“About 60% of adults over 65 have two or more chronic conditions, of which depression is the single most common comorbidity,” Dr. Alpert, chair of the department of psychiatry and behavioral sciences at the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, said during an annual psychopharmacology update held by the Nevada Psychiatric Association.

“Premorbid depression is a risk factor for a number of medical conditions, such as heart disease. We also know that medical illness is a risk factor for depression. Comorbid depression predicts poorer health outcomes, including disability, hospital readmission, and mortality. It is also associated with up to severalfold higher general medical costs.”

Despite the pervasive nature of depression on other medical conditions, a limited evidence base exists to guide clinicians on treatment approaches.

“Most major depressive disorder randomized clinical trials exclude individuals with active medical illness, but we do know that medical comorbidity is associated with poorer depression outcomes,” Dr. Alpert said. For example, the STAR*D trial found that people with major depressive disorder plus medical comorbidity had lower remission rates, compared with those who had MDD alone (P < .001), while a large analysis from University of Pittsburgh researchers found that people with medical comorbidities had higher depression recurrence rates.

An assessment of the relationship between medical conditions and depression should include thinking about the association between the medical illness itself and medications with depressive symptoms.

“Are the medications contributing to depressive symptoms?” he asked. “We also want to be thinking of the impact of medical illness and medications on antidepressant pharmacokinetics and pharmacodynamics. We also want to know about the evidence for antidepressant safety, tolerability, efficacy, and anticipated drug-drug interactions among individuals with the medical illness. You also want to enhance focus on treatment adherence and coordination of care.”

Nontraditional routes of antidepressant administration exist for patients who have difficulty swallowing pills. Food and Drug Administration–approved options include transdermal selegiline; intranasal esketamine; liquid forms of fluoxetine, escitalopram, paroxetine, nortriptyline, doxepin, imipramine, and lithium; and oral disintegrating tablet forms of mirtazapine and selegiline. As for non–FDA-approved forms of antidepressant administration, small studies or case reports have appeared in the medical literature regarding intravenous ketamine, citalopram, amitriptyline, mirtazapine, maprotiline, and lithium; intramuscular ketamine and amitriptyline; and rectal forms of antidepressants such as trazodone, amitriptyline, doxepin, fluoxetine, and lamotrigine.

“It’s good to keep in mind that, when you’re not able to use by mouth antidepressants or typical tablet forms of antidepressants, there are other options available,” said Dr. Alpert, who is also chair of the American Psychiatric Association’s Council on Research.

Metabolism of medications occurs primarily in the liver, he continued, but some metabolic enzymes also line the intestinal tract. The metabolism of a substrate may be inhibited or induced by other drugs.

“If someone is on drug A and we give drug B, and drug B is inhibiting the metabolism of drug A, there will be a very rapid impact – hours to just a few days,” Dr. Alpert said. “The substrate levels rise very quickly, so within hours or days of taking drug B, drug A levels can rise steeply.” On the other hand, if someone is on drug A and you give a drug B – which induces the enzymes that usually metabolize drug A – the impact will be gradual. “That’s because induction requires increased synthesis of the metabolic enzyme responsible for metabolizing drug A,” he said. “That happens over days to weeks.”

Medications that are potential inducers of metabolism include carbamazepine, phenobarbital, phenytoin, primidone, prednisone, ritonavir, rifampin, chronic alcohol use, chronic smoking, St. John’s wort, and consumption of large quantities of cruciferous vegetables and charbroiled meats.

On the other hand, potential inhibitors of metabolism include antifungals, macrolide antibiotics, fluoroquinolones, antiretrovirals, isoniazid, antimalarials, disulfiram, SSRIs, phenothiazines, valproic acid, nefazodone, duloxetine, bupropion, beta-blockers, acute alcohol use, cimetidine, quinidine, calcium channel blockers, grapefruit juice, propafenone, and amiodarone.

“When treating people with significant medical comorbidity, start low and go slow, but persevere,” Dr. Alpert advised. “We want to always think about the risk of treating versus the risk of not treating, or not treating actively enough. Often, people with comorbid medical illness require the same or even more assertive treatment with pharmacotherapy for their depression as people without medical illness. So, we don’t want to make the mistake of undertreating depression. We also want to anticipate and address challenges with adherence.”

He also recommended being mindful of the most salient side effects for a given condition, such as lowered seizure threshold or QT prolongation in populations with brain injury or with cardiovascular disease, and to leverage dual benefits when they might exist, such as using [selective norepinephrine reuptake inhibitors] for depression and pain or hot flashes, or bupropion for depression and smoking cessation, or mirtazapine, which is effective for nausea, cachexia, or insomnia, as well as depression itself.

“We want to collaborate closely and regularly with other treaters, sharing our notes and diagnostic impressions,” Dr. Alpert said. “We want to use all the tools in the box in addition to pharmacotherapy, thinking about psychotherapy, neuromodulation, and peer navigators. We want to strive for measurement-based care using rating scales when we can, to augment our treatment. And we want to be resourceful. There are very few absolute contraindications in treating the medically ill.”

Dr. Alpert reports having received speaker’s honoraria, consulting fees, and research support from numerous pharmaceutical companies.

dbrunk@mdedge.com

For many adults, depression and chronic medical conditions are inextricably linked.

In fact, the prevalence of depression is 2-10 times higher among people with chronic medical conditions, particularly in people with chronic pain, where the prevalence reaches 40%-60%, according to Jonathan E. Alpert, MD, PhD.

“About 60% of adults over 65 have two or more chronic conditions, of which depression is the single most common comorbidity,” Dr. Alpert, chair of the department of psychiatry and behavioral sciences at the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, said during an annual psychopharmacology update held by the Nevada Psychiatric Association.

“Premorbid depression is a risk factor for a number of medical conditions, such as heart disease. We also know that medical illness is a risk factor for depression. Comorbid depression predicts poorer health outcomes, including disability, hospital readmission, and mortality. It is also associated with up to severalfold higher general medical costs.”

Despite the pervasive nature of depression on other medical conditions, a limited evidence base exists to guide clinicians on treatment approaches.

“Most major depressive disorder randomized clinical trials exclude individuals with active medical illness, but we do know that medical comorbidity is associated with poorer depression outcomes,” Dr. Alpert said. For example, the STAR*D trial found that people with major depressive disorder plus medical comorbidity had lower remission rates, compared with those who had MDD alone (P < .001), while a large analysis from University of Pittsburgh researchers found that people with medical comorbidities had higher depression recurrence rates.

An assessment of the relationship between medical conditions and depression should include thinking about the association between the medical illness itself and medications with depressive symptoms.

“Are the medications contributing to depressive symptoms?” he asked. “We also want to be thinking of the impact of medical illness and medications on antidepressant pharmacokinetics and pharmacodynamics. We also want to know about the evidence for antidepressant safety, tolerability, efficacy, and anticipated drug-drug interactions among individuals with the medical illness. You also want to enhance focus on treatment adherence and coordination of care.”

Nontraditional routes of antidepressant administration exist for patients who have difficulty swallowing pills. Food and Drug Administration–approved options include transdermal selegiline; intranasal esketamine; liquid forms of fluoxetine, escitalopram, paroxetine, nortriptyline, doxepin, imipramine, and lithium; and oral disintegrating tablet forms of mirtazapine and selegiline. As for non–FDA-approved forms of antidepressant administration, small studies or case reports have appeared in the medical literature regarding intravenous ketamine, citalopram, amitriptyline, mirtazapine, maprotiline, and lithium; intramuscular ketamine and amitriptyline; and rectal forms of antidepressants such as trazodone, amitriptyline, doxepin, fluoxetine, and lamotrigine.

“It’s good to keep in mind that, when you’re not able to use by mouth antidepressants or typical tablet forms of antidepressants, there are other options available,” said Dr. Alpert, who is also chair of the American Psychiatric Association’s Council on Research.

Metabolism of medications occurs primarily in the liver, he continued, but some metabolic enzymes also line the intestinal tract. The metabolism of a substrate may be inhibited or induced by other drugs.

“If someone is on drug A and we give drug B, and drug B is inhibiting the metabolism of drug A, there will be a very rapid impact – hours to just a few days,” Dr. Alpert said. “The substrate levels rise very quickly, so within hours or days of taking drug B, drug A levels can rise steeply.” On the other hand, if someone is on drug A and you give a drug B – which induces the enzymes that usually metabolize drug A – the impact will be gradual. “That’s because induction requires increased synthesis of the metabolic enzyme responsible for metabolizing drug A,” he said. “That happens over days to weeks.”

Medications that are potential inducers of metabolism include carbamazepine, phenobarbital, phenytoin, primidone, prednisone, ritonavir, rifampin, chronic alcohol use, chronic smoking, St. John’s wort, and consumption of large quantities of cruciferous vegetables and charbroiled meats.

On the other hand, potential inhibitors of metabolism include antifungals, macrolide antibiotics, fluoroquinolones, antiretrovirals, isoniazid, antimalarials, disulfiram, SSRIs, phenothiazines, valproic acid, nefazodone, duloxetine, bupropion, beta-blockers, acute alcohol use, cimetidine, quinidine, calcium channel blockers, grapefruit juice, propafenone, and amiodarone.

“When treating people with significant medical comorbidity, start low and go slow, but persevere,” Dr. Alpert advised. “We want to always think about the risk of treating versus the risk of not treating, or not treating actively enough. Often, people with comorbid medical illness require the same or even more assertive treatment with pharmacotherapy for their depression as people without medical illness. So, we don’t want to make the mistake of undertreating depression. We also want to anticipate and address challenges with adherence.”

He also recommended being mindful of the most salient side effects for a given condition, such as lowered seizure threshold or QT prolongation in populations with brain injury or with cardiovascular disease, and to leverage dual benefits when they might exist, such as using [selective norepinephrine reuptake inhibitors] for depression and pain or hot flashes, or bupropion for depression and smoking cessation, or mirtazapine, which is effective for nausea, cachexia, or insomnia, as well as depression itself.

“We want to collaborate closely and regularly with other treaters, sharing our notes and diagnostic impressions,” Dr. Alpert said. “We want to use all the tools in the box in addition to pharmacotherapy, thinking about psychotherapy, neuromodulation, and peer navigators. We want to strive for measurement-based care using rating scales when we can, to augment our treatment. And we want to be resourceful. There are very few absolute contraindications in treating the medically ill.”

Dr. Alpert reports having received speaker’s honoraria, consulting fees, and research support from numerous pharmaceutical companies.

dbrunk@mdedge.com

For many adults, depression and chronic medical conditions are inextricably linked.

In fact, the prevalence of depression is 2-10 times higher among people with chronic medical conditions, particularly in people with chronic pain, where the prevalence reaches 40%-60%, according to Jonathan E. Alpert, MD, PhD.

“About 60% of adults over 65 have two or more chronic conditions, of which depression is the single most common comorbidity,” Dr. Alpert, chair of the department of psychiatry and behavioral sciences at the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, said during an annual psychopharmacology update held by the Nevada Psychiatric Association.

“Premorbid depression is a risk factor for a number of medical conditions, such as heart disease. We also know that medical illness is a risk factor for depression. Comorbid depression predicts poorer health outcomes, including disability, hospital readmission, and mortality. It is also associated with up to severalfold higher general medical costs.”

Despite the pervasive nature of depression on other medical conditions, a limited evidence base exists to guide clinicians on treatment approaches.

“Most major depressive disorder randomized clinical trials exclude individuals with active medical illness, but we do know that medical comorbidity is associated with poorer depression outcomes,” Dr. Alpert said. For example, the STAR*D trial found that people with major depressive disorder plus medical comorbidity had lower remission rates, compared with those who had MDD alone (P < .001), while a large analysis from University of Pittsburgh researchers found that people with medical comorbidities had higher depression recurrence rates.

An assessment of the relationship between medical conditions and depression should include thinking about the association between the medical illness itself and medications with depressive symptoms.

“Are the medications contributing to depressive symptoms?” he asked. “We also want to be thinking of the impact of medical illness and medications on antidepressant pharmacokinetics and pharmacodynamics. We also want to know about the evidence for antidepressant safety, tolerability, efficacy, and anticipated drug-drug interactions among individuals with the medical illness. You also want to enhance focus on treatment adherence and coordination of care.”

Nontraditional routes of antidepressant administration exist for patients who have difficulty swallowing pills. Food and Drug Administration–approved options include transdermal selegiline; intranasal esketamine; liquid forms of fluoxetine, escitalopram, paroxetine, nortriptyline, doxepin, imipramine, and lithium; and oral disintegrating tablet forms of mirtazapine and selegiline. As for non–FDA-approved forms of antidepressant administration, small studies or case reports have appeared in the medical literature regarding intravenous ketamine, citalopram, amitriptyline, mirtazapine, maprotiline, and lithium; intramuscular ketamine and amitriptyline; and rectal forms of antidepressants such as trazodone, amitriptyline, doxepin, fluoxetine, and lamotrigine.

“It’s good to keep in mind that, when you’re not able to use by mouth antidepressants or typical tablet forms of antidepressants, there are other options available,” said Dr. Alpert, who is also chair of the American Psychiatric Association’s Council on Research.

Metabolism of medications occurs primarily in the liver, he continued, but some metabolic enzymes also line the intestinal tract. The metabolism of a substrate may be inhibited or induced by other drugs.

“If someone is on drug A and we give drug B, and drug B is inhibiting the metabolism of drug A, there will be a very rapid impact – hours to just a few days,” Dr. Alpert said. “The substrate levels rise very quickly, so within hours or days of taking drug B, drug A levels can rise steeply.” On the other hand, if someone is on drug A and you give a drug B – which induces the enzymes that usually metabolize drug A – the impact will be gradual. “That’s because induction requires increased synthesis of the metabolic enzyme responsible for metabolizing drug A,” he said. “That happens over days to weeks.”

Medications that are potential inducers of metabolism include carbamazepine, phenobarbital, phenytoin, primidone, prednisone, ritonavir, rifampin, chronic alcohol use, chronic smoking, St. John’s wort, and consumption of large quantities of cruciferous vegetables and charbroiled meats.

On the other hand, potential inhibitors of metabolism include antifungals, macrolide antibiotics, fluoroquinolones, antiretrovirals, isoniazid, antimalarials, disulfiram, SSRIs, phenothiazines, valproic acid, nefazodone, duloxetine, bupropion, beta-blockers, acute alcohol use, cimetidine, quinidine, calcium channel blockers, grapefruit juice, propafenone, and amiodarone.

“When treating people with significant medical comorbidity, start low and go slow, but persevere,” Dr. Alpert advised. “We want to always think about the risk of treating versus the risk of not treating, or not treating actively enough. Often, people with comorbid medical illness require the same or even more assertive treatment with pharmacotherapy for their depression as people without medical illness. So, we don’t want to make the mistake of undertreating depression. We also want to anticipate and address challenges with adherence.”

He also recommended being mindful of the most salient side effects for a given condition, such as lowered seizure threshold or QT prolongation in populations with brain injury or with cardiovascular disease, and to leverage dual benefits when they might exist, such as using [selective norepinephrine reuptake inhibitors] for depression and pain or hot flashes, or bupropion for depression and smoking cessation, or mirtazapine, which is effective for nausea, cachexia, or insomnia, as well as depression itself.

“We want to collaborate closely and regularly with other treaters, sharing our notes and diagnostic impressions,” Dr. Alpert said. “We want to use all the tools in the box in addition to pharmacotherapy, thinking about psychotherapy, neuromodulation, and peer navigators. We want to strive for measurement-based care using rating scales when we can, to augment our treatment. And we want to be resourceful. There are very few absolute contraindications in treating the medically ill.”

Dr. Alpert reports having received speaker’s honoraria, consulting fees, and research support from numerous pharmaceutical companies.

dbrunk@mdedge.com

Despite their similar functions, each current and emerging therapy for treating hemophilia has a unique safety profile, and each needs to be weighed apart from agents both within and outside its pharmacologic class, a hemophilia specialist said.

“My view is that each new molecule coming to the hemophilia space, including variant factor molecules, needs to be scrutinized separately, without class assumptions or extrapolations, and it’s clear that thrombosis risk has become a priority safety consideration,” said Dan Hart, MBChB, MRCP, FRCPath, PhD, from Barts and the London School of Medicine and Dentistry.

He reviewed the comparative safety of standard and novel therapies for hemophilia at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

Factor inhibitors

Inhibitors occur in both hemophilia A and hemophilia B, and are primarily seen in patients with childhood exposure to factor concentrates. Inhibitors, which include anti–factor VIII and factor IX alloantibodies, are more common among patients with severe hemophilia and those with more disruptive factor VIII and factor IX mutations.

“There can be transient vs. persistent inhibitors, and arguably the more you look, the more you find, but clinically we never miss high-titer inhibitors that have a big impact on individuals and the subsequent decisions about management,” he said.
 

Hamster vs. human

It’s currently unclear whether there is an immunologic advantage for previously untreated patients to be started on factor VIII concentrates derived from recombinant human cells lines, or from products derived from Chinese hamster ovary (CHO) or baby hamster kidney (BHK) cell lines, Dr. Hart said.

“We need to ensure that we’re not selective about comparator choice for new products in the absence of head-to-head studies,” he said.
 

Route of administration matters

Inhibitors appear to be a more common occurrence among patients who received factor concentrates subcutaneously, compared with intravenously, Dr. Hart noted, pointing to a 2011 study indicating a background annual risk of 5 cases of inhibitor development per 1,000 treatment years in previously treated patients who received intravenous therapy (Blood. 2011 Jun 9;117[23]:6367-70).

In contrast, in a phase 1 trial of subcutaneous turoctocog alfa pegol, 5 out of 26 patients had detectable N8-GP–binding antibodies after 42-91 exposure days. Of these patients, one developed an inhibitor to factor VIII, and anti–N8-GP antibody appearance was associated with a decline in factor VIII plasma activity in four of the five patients. In addition, five patients reported a total of nine bleeding episodes requiring treatment during prophylaxis. As a result of this trial, further clinical development of the subcutaneous version was suspended. (J Thromb Haemost. 2020 Feb;18[2]:341-51).

Other subcutaneously administered factors are currently in development, Dr. Hart noted.
 

Nonfactor inhibitors?

“The nonfactor agents do have the risk of generating antibodies: Monoclonal antibodies outside the hemophilia setting provoke antidrug antibodies,” he said.

Although there is no consensus regarding which assay can best monitor antidrug antibodies (ADA), enzyme-linked immunosorbent assay (ELISA) can detect neutralizing antibodies and other antibodies.

In the hemophilia setting, surrogate markers for loss of drug efficacy include longer activated partial thromboplastin time (ATTP) or a drop in serum drug levels. Worsening bleeding phenotype can also be a marker for loss of efficacy, albeit an imperfect one.

Emicizumab (Hemlibara), the first nonfactor monoclonal agent to make it to market, has the largest dataset available, and evidence suggests a rate of neutralizing antibodies with this agent of less than 1% in the HAVEN clinical trial series, but 5.2% in the single-arm STASEY trial.

“We shouldn’t assume that other biophenotypics will have a similar ADA rate, and this needs to be evaluated for each molecule, as it will need to be for other monoclonals” such as anti–tissue factor pathway (TFPI) antibodies, Dr. Hart emphasized.
 

Pegylation

Pegylated compounds include polyethylene glycol, an inert polymer, covalently bound to the therapeutic protein to extend its half-life, and theoretically, reduce immunogenicity.

Many patients may already have exposure to pegylated products in the form of peginterferon to treat hepatitis C, consumer products such as toothpaste, cough medicine, and cosmetics, and, more recently, in vaccines against COVID-19.

Safety considerations with pegylated agents in hemophilia include concerns about accumulation of polyethylene glycol (PEG), although “some of the preclinical models looking at excretion of PEG are difficult to interpret in my view, and people debate about whether studies are long enough, but it’s undoubtedly the case that toxicology dosing is order of magnitude higher than the routine dosing in hemophilia,” he said.

After more than 5 years of experience with pegylated products there is no clinical evidence of concern, although “it’s not clear, actually, what we’re looking for, whether it’s a clinical parameter, or imaging or histological parameter.”

Patients may also not have lifelong exposure to pegylated products, as it is unlikely that they will stay on the same product for decades, Dr. Hart said.
 

Thrombosis

As of June 30, 2020, more than 7,200 persons with hemophilia have received emicizumab, and there have been 23 reported thrombotic events, 19 of which occurred in the postmarketing period. Of the reported cases, six patients had a myocardial infarction, and all of these patients had at least one cardiovascular risk factor.

The antithrombin agent fitusiran was associated with one fatal thrombotic event in a phase 2, open-label extension trial, leading to a pause and resumption with mitigation protocols, but that trial has since been paused again because of additional, nonfatal thrombotic events.

Nonfatal thrombotic events have also occurred in clinical trials for the investigational anti-TFPI monoclonal antibodies BAY 1093884 and concizumab, but none have thus far been reported in phase 3 trial of marstacimab.

“We need renewed efforts for prospective reporting and independent review of all adverse events of all agents, old and new: This will need some guidance nationally and internationally, and I think the relevant trial [serious adverse events] need to be reported in peer review literature, and clinicaltrials.gov updated in a timely manner, regardless of whether that strategy was successful or unsuccessful,” Dr. Hart said.
 

Risk with longer-acting agents?

In the question and answer following his presentation, Christoph Königs, MD, PhD, from University Hospital Frankfurt, asked whether there was potential for increased thrombosis risk with second-generation extended half-life (EHL) molecules in clinical trials.

“As we edge towards normalization of hemostasis, clearly the other non–hemophilia dependent issues of thrombosis risk come into play,” Dr. Hart acknowledged. “I think it will be an inevitability that there will be events, and we need to understand what the denominators are – hence my pitch for there being a renewed effort to try and collate sufficient data that we can really define events happening with people treated with standard half-life [products] through into the novel agents,” he said.

Dr. Hart disclosed grant/research support and speaker bureau activities for Bayer, Octapharma, Takeda, and others. Dr. Königs has reported no relevant disclosures.

Despite their similar functions, each current and emerging therapy for treating hemophilia has a unique safety profile, and each needs to be weighed apart from agents both within and outside its pharmacologic class, a hemophilia specialist said.

“My view is that each new molecule coming to the hemophilia space, including variant factor molecules, needs to be scrutinized separately, without class assumptions or extrapolations, and it’s clear that thrombosis risk has become a priority safety consideration,” said Dan Hart, MBChB, MRCP, FRCPath, PhD, from Barts and the London School of Medicine and Dentistry.

He reviewed the comparative safety of standard and novel therapies for hemophilia at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

Factor inhibitors

Inhibitors occur in both hemophilia A and hemophilia B, and are primarily seen in patients with childhood exposure to factor concentrates. Inhibitors, which include anti–factor VIII and factor IX alloantibodies, are more common among patients with severe hemophilia and those with more disruptive factor VIII and factor IX mutations.

“There can be transient vs. persistent inhibitors, and arguably the more you look, the more you find, but clinically we never miss high-titer inhibitors that have a big impact on individuals and the subsequent decisions about management,” he said.
 

Hamster vs. human

It’s currently unclear whether there is an immunologic advantage for previously untreated patients to be started on factor VIII concentrates derived from recombinant human cells lines, or from products derived from Chinese hamster ovary (CHO) or baby hamster kidney (BHK) cell lines, Dr. Hart said.

“We need to ensure that we’re not selective about comparator choice for new products in the absence of head-to-head studies,” he said.
 

Route of administration matters

Inhibitors appear to be a more common occurrence among patients who received factor concentrates subcutaneously, compared with intravenously, Dr. Hart noted, pointing to a 2011 study indicating a background annual risk of 5 cases of inhibitor development per 1,000 treatment years in previously treated patients who received intravenous therapy (Blood. 2011 Jun 9;117[23]:6367-70).

In contrast, in a phase 1 trial of subcutaneous turoctocog alfa pegol, 5 out of 26 patients had detectable N8-GP–binding antibodies after 42-91 exposure days. Of these patients, one developed an inhibitor to factor VIII, and anti–N8-GP antibody appearance was associated with a decline in factor VIII plasma activity in four of the five patients. In addition, five patients reported a total of nine bleeding episodes requiring treatment during prophylaxis. As a result of this trial, further clinical development of the subcutaneous version was suspended. (J Thromb Haemost. 2020 Feb;18[2]:341-51).

Other subcutaneously administered factors are currently in development, Dr. Hart noted.
 

Nonfactor inhibitors?

“The nonfactor agents do have the risk of generating antibodies: Monoclonal antibodies outside the hemophilia setting provoke antidrug antibodies,” he said.

Although there is no consensus regarding which assay can best monitor antidrug antibodies (ADA), enzyme-linked immunosorbent assay (ELISA) can detect neutralizing antibodies and other antibodies.

In the hemophilia setting, surrogate markers for loss of drug efficacy include longer activated partial thromboplastin time (ATTP) or a drop in serum drug levels. Worsening bleeding phenotype can also be a marker for loss of efficacy, albeit an imperfect one.

Emicizumab (Hemlibara), the first nonfactor monoclonal agent to make it to market, has the largest dataset available, and evidence suggests a rate of neutralizing antibodies with this agent of less than 1% in the HAVEN clinical trial series, but 5.2% in the single-arm STASEY trial.

“We shouldn’t assume that other biophenotypics will have a similar ADA rate, and this needs to be evaluated for each molecule, as it will need to be for other monoclonals” such as anti–tissue factor pathway (TFPI) antibodies, Dr. Hart emphasized.
 

Pegylation

Pegylated compounds include polyethylene glycol, an inert polymer, covalently bound to the therapeutic protein to extend its half-life, and theoretically, reduce immunogenicity.

Many patients may already have exposure to pegylated products in the form of peginterferon to treat hepatitis C, consumer products such as toothpaste, cough medicine, and cosmetics, and, more recently, in vaccines against COVID-19.

Safety considerations with pegylated agents in hemophilia include concerns about accumulation of polyethylene glycol (PEG), although “some of the preclinical models looking at excretion of PEG are difficult to interpret in my view, and people debate about whether studies are long enough, but it’s undoubtedly the case that toxicology dosing is order of magnitude higher than the routine dosing in hemophilia,” he said.

After more than 5 years of experience with pegylated products there is no clinical evidence of concern, although “it’s not clear, actually, what we’re looking for, whether it’s a clinical parameter, or imaging or histological parameter.”

Patients may also not have lifelong exposure to pegylated products, as it is unlikely that they will stay on the same product for decades, Dr. Hart said.
 

Thrombosis

As of June 30, 2020, more than 7,200 persons with hemophilia have received emicizumab, and there have been 23 reported thrombotic events, 19 of which occurred in the postmarketing period. Of the reported cases, six patients had a myocardial infarction, and all of these patients had at least one cardiovascular risk factor.

The antithrombin agent fitusiran was associated with one fatal thrombotic event in a phase 2, open-label extension trial, leading to a pause and resumption with mitigation protocols, but that trial has since been paused again because of additional, nonfatal thrombotic events.

Nonfatal thrombotic events have also occurred in clinical trials for the investigational anti-TFPI monoclonal antibodies BAY 1093884 and concizumab, but none have thus far been reported in phase 3 trial of marstacimab.

“We need renewed efforts for prospective reporting and independent review of all adverse events of all agents, old and new: This will need some guidance nationally and internationally, and I think the relevant trial [serious adverse events] need to be reported in peer review literature, and clinicaltrials.gov updated in a timely manner, regardless of whether that strategy was successful or unsuccessful,” Dr. Hart said.
 

Risk with longer-acting agents?

In the question and answer following his presentation, Christoph Königs, MD, PhD, from University Hospital Frankfurt, asked whether there was potential for increased thrombosis risk with second-generation extended half-life (EHL) molecules in clinical trials.

“As we edge towards normalization of hemostasis, clearly the other non–hemophilia dependent issues of thrombosis risk come into play,” Dr. Hart acknowledged. “I think it will be an inevitability that there will be events, and we need to understand what the denominators are – hence my pitch for there being a renewed effort to try and collate sufficient data that we can really define events happening with people treated with standard half-life [products] through into the novel agents,” he said.

Dr. Hart disclosed grant/research support and speaker bureau activities for Bayer, Octapharma, Takeda, and others. Dr. Königs has reported no relevant disclosures.

Despite their similar functions, each current and emerging therapy for treating hemophilia has a unique safety profile, and each needs to be weighed apart from agents both within and outside its pharmacologic class, a hemophilia specialist said.

“My view is that each new molecule coming to the hemophilia space, including variant factor molecules, needs to be scrutinized separately, without class assumptions or extrapolations, and it’s clear that thrombosis risk has become a priority safety consideration,” said Dan Hart, MBChB, MRCP, FRCPath, PhD, from Barts and the London School of Medicine and Dentistry.

He reviewed the comparative safety of standard and novel therapies for hemophilia at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

Factor inhibitors

Inhibitors occur in both hemophilia A and hemophilia B, and are primarily seen in patients with childhood exposure to factor concentrates. Inhibitors, which include anti–factor VIII and factor IX alloantibodies, are more common among patients with severe hemophilia and those with more disruptive factor VIII and factor IX mutations.

“There can be transient vs. persistent inhibitors, and arguably the more you look, the more you find, but clinically we never miss high-titer inhibitors that have a big impact on individuals and the subsequent decisions about management,” he said.
 

Hamster vs. human

It’s currently unclear whether there is an immunologic advantage for previously untreated patients to be started on factor VIII concentrates derived from recombinant human cells lines, or from products derived from Chinese hamster ovary (CHO) or baby hamster kidney (BHK) cell lines, Dr. Hart said.

“We need to ensure that we’re not selective about comparator choice for new products in the absence of head-to-head studies,” he said.
 

Route of administration matters

Inhibitors appear to be a more common occurrence among patients who received factor concentrates subcutaneously, compared with intravenously, Dr. Hart noted, pointing to a 2011 study indicating a background annual risk of 5 cases of inhibitor development per 1,000 treatment years in previously treated patients who received intravenous therapy (Blood. 2011 Jun 9;117[23]:6367-70).

In contrast, in a phase 1 trial of subcutaneous turoctocog alfa pegol, 5 out of 26 patients had detectable N8-GP–binding antibodies after 42-91 exposure days. Of these patients, one developed an inhibitor to factor VIII, and anti–N8-GP antibody appearance was associated with a decline in factor VIII plasma activity in four of the five patients. In addition, five patients reported a total of nine bleeding episodes requiring treatment during prophylaxis. As a result of this trial, further clinical development of the subcutaneous version was suspended. (J Thromb Haemost. 2020 Feb;18[2]:341-51).

Other subcutaneously administered factors are currently in development, Dr. Hart noted.
 

Nonfactor inhibitors?

“The nonfactor agents do have the risk of generating antibodies: Monoclonal antibodies outside the hemophilia setting provoke antidrug antibodies,” he said.

Although there is no consensus regarding which assay can best monitor antidrug antibodies (ADA), enzyme-linked immunosorbent assay (ELISA) can detect neutralizing antibodies and other antibodies.

In the hemophilia setting, surrogate markers for loss of drug efficacy include longer activated partial thromboplastin time (ATTP) or a drop in serum drug levels. Worsening bleeding phenotype can also be a marker for loss of efficacy, albeit an imperfect one.

Emicizumab (Hemlibara), the first nonfactor monoclonal agent to make it to market, has the largest dataset available, and evidence suggests a rate of neutralizing antibodies with this agent of less than 1% in the HAVEN clinical trial series, but 5.2% in the single-arm STASEY trial.

“We shouldn’t assume that other biophenotypics will have a similar ADA rate, and this needs to be evaluated for each molecule, as it will need to be for other monoclonals” such as anti–tissue factor pathway (TFPI) antibodies, Dr. Hart emphasized.
 

Pegylation

Pegylated compounds include polyethylene glycol, an inert polymer, covalently bound to the therapeutic protein to extend its half-life, and theoretically, reduce immunogenicity.

Many patients may already have exposure to pegylated products in the form of peginterferon to treat hepatitis C, consumer products such as toothpaste, cough medicine, and cosmetics, and, more recently, in vaccines against COVID-19.

Safety considerations with pegylated agents in hemophilia include concerns about accumulation of polyethylene glycol (PEG), although “some of the preclinical models looking at excretion of PEG are difficult to interpret in my view, and people debate about whether studies are long enough, but it’s undoubtedly the case that toxicology dosing is order of magnitude higher than the routine dosing in hemophilia,” he said.

After more than 5 years of experience with pegylated products there is no clinical evidence of concern, although “it’s not clear, actually, what we’re looking for, whether it’s a clinical parameter, or imaging or histological parameter.”

Patients may also not have lifelong exposure to pegylated products, as it is unlikely that they will stay on the same product for decades, Dr. Hart said.
 

Thrombosis

As of June 30, 2020, more than 7,200 persons with hemophilia have received emicizumab, and there have been 23 reported thrombotic events, 19 of which occurred in the postmarketing period. Of the reported cases, six patients had a myocardial infarction, and all of these patients had at least one cardiovascular risk factor.

The antithrombin agent fitusiran was associated with one fatal thrombotic event in a phase 2, open-label extension trial, leading to a pause and resumption with mitigation protocols, but that trial has since been paused again because of additional, nonfatal thrombotic events.

Nonfatal thrombotic events have also occurred in clinical trials for the investigational anti-TFPI monoclonal antibodies BAY 1093884 and concizumab, but none have thus far been reported in phase 3 trial of marstacimab.

“We need renewed efforts for prospective reporting and independent review of all adverse events of all agents, old and new: This will need some guidance nationally and internationally, and I think the relevant trial [serious adverse events] need to be reported in peer review literature, and clinicaltrials.gov updated in a timely manner, regardless of whether that strategy was successful or unsuccessful,” Dr. Hart said.
 

Risk with longer-acting agents?

In the question and answer following his presentation, Christoph Königs, MD, PhD, from University Hospital Frankfurt, asked whether there was potential for increased thrombosis risk with second-generation extended half-life (EHL) molecules in clinical trials.

“As we edge towards normalization of hemostasis, clearly the other non–hemophilia dependent issues of thrombosis risk come into play,” Dr. Hart acknowledged. “I think it will be an inevitability that there will be events, and we need to understand what the denominators are – hence my pitch for there being a renewed effort to try and collate sufficient data that we can really define events happening with people treated with standard half-life [products] through into the novel agents,” he said.

Dr. Hart disclosed grant/research support and speaker bureau activities for Bayer, Octapharma, Takeda, and others. Dr. Königs has reported no relevant disclosures.

More than 50% of health care workers infected with SARS-CoV-2 report that their sense of smell has not returned to normal an average of 5 months post infection, new research shows.

Nenad Cavoski/iStock/Getty Images Plus

The findings illustrate that olfactory problems are common not only during the acute COVID-19 phase but also “in the long run” and that these problems should be “taken into consideration” when following up these patients, study investigator Johannes Frasnelli, MD, professor, department of anatomy, Université du Québec à Trois-Rivières, said in an interview.

Loss of the sense of smell can affect quality of life because it affects eating and drinking, and may even be dangerous, said Dr. Frasnelli. “If your sense of smell is impaired, you may unknowingly eat spoiled food, or you may not smell smoke or gas in your home,” he said. In addition, Dr. Frasnelli noted that an impaired sense of smell is associated with higher rates of depression. The findings will be presented at the annual meeting of the American Academy of Neurology in April.

‘Striking’ finding

Research shows that about 60% of patients with COVID-19 lose their sense of smell to some degree during the acute phase of the disease. “But we wanted to go further and look at the longer-term effects of loss of smell and taste,” said Dr. Frasnelli.

The analysis included 813 health care workers in the province of Quebec. For all the patients, SARS-CoV-2 infection was confirmed through testing with a nasopharyngeal viral swab.

Participants completed a 64-item online questionnaire that asked about three senses: olfactory; gustatory, which includes tastes such as sweet, sour, bitter, salty, savory and umami; and trigeminal, which includes sensations such as spiciness of hot peppers and “coolness” of mint.

They were asked to rate these on a scale of 0 (no perception) to 10 (very strong perception) before the infection, during the infection, and currently. They were also asked about other symptoms, including fatigue.

Most respondents had been infected in the first wave of the virus in March and April of 2020 and responded to the questionnaire an average of 5 months later.

The vast majority of respondents (84.1%) were women, which Dr. Frasnelli said was not surprising because women predominate in the health care field.

The analysis showed that average smell ratings were 8.98 before infection, 2.85 during the acute phase, and 7.41 when respondents answered the questionnaire. The sense of taste was less affected and recovered faster than did the sense of smell. Results for taste were 9.20 before infection, 3.59 during the acute phase, and 8.05 after COVID-19.

Among 580 respondents who indicated a compromised sense of smell during the acute phase, the average smell rating when answering the questionnaire was 6.89, compared to 9.03 before the infection. More than half (51.2%) reported not regaining full olfactory function.

The fact that the sense of smell had not returned to normal for half the participants so long after being infected is “novel and quite striking,” said Dr. Frasnelli.

However, he noted, this doesn’t necessarily mean all those with a compromised sense of smell “have huge problems.” In some cases, he said, the problem “is more subtle.”
 

Not a CNS problem?

Respondents also completed a chemosensory dysfunction home test (CD-HT). They were asked to prepare common household food items, such as peanut butter, sugar, salt, and vinegar, in a particular way – for example, to add sugar or salt to water – and provide feedback on how they smell and taste.

For this CD-HT analysis, 18.4% of respondents reported having persistent loss of smell. This, Dr. Frasnelli said, adds to evidence from self-reported responses and suggests that in some cases, the problem is more than senses not returning to normal.

“From the questionnaires, roughly 50% said their sense of smell is still not back to normal, and when we look at the CD home test, we see that almost 20% of subjects indeed have pretty strong impairment of their sense of smell,” he said.

The results showed no sex differences, although Dr. Frasnelli noted that most of the sample were women. “It’s tricky to look at the data with regard to sex because it’s a bit skewed,” he said.

Male respondents were older than female participants, but there was no difference in impairment between age groups. Dr. Frasnelli said this was “quite interesting,” inasmuch as older people usually lose some sense of smell.

The researchers have not yet examined whether the results differ by type of health care worker.

They also have not examined in detail whether infection severity affects the risk for extended olfactory impairment. Although some research suggests that the problem with smell is more common in less severe cases, Dr. Frasnelli noted this could be because loss of smell is not a huge problem for patients battling grave health problems.

As for other symptoms, many respondents reported lingering fatigue; some reported debilitating fatigue, said Dr. Frasnelli. However, he cautioned that this is difficult to interpret, because the participants were health care workers, many of whom returned to work during the pandemic and perhaps had not fully rested.

He also noted that he and his colleagues have not “made the link” between impaired smell and the degree of fatigue.

The COVID-19 virus appears to attack supporting sustentacular cells in the olfactory epithelium, not nerve cells.

“Right now, it seems that the smell problem is not a central nervous system problem but a peripheral problem,” said Dr. Frasnelli. “But we don’t know for sure; it may be that the virus somehow gets into the brain and some symptoms are caused by the effects of the infection on the brain.”

The researchers will extend their research with another questionnaire to assess senses 10-12 months after COVID-19.

Limitations of the study include the subjective nature of the smell and taste ratings and the single time point at which data were collected.
 

Confirmatory findings

Commenting on the research in an interview, Thomas Hummel, MD, professor, smell and taste clinic, department of otorhinolaryngology, Technische Universität Dresden (Germany), said the new results regarding loss of smell after COVID-19 are “very congruent” with what he and his colleagues have observed.

Research shows that up to one in five of those infected with SARS-CoV-2 experience olfactory loss. “While the numbers may vary a bit from study to study or lab to lab, I think 5% to 20% of post–COVID-19 patients exhibit long-term olfactory loss,” Dr. Hummel said.

His group has observed that “many more are not back to normal,” which conforms with what Dr. Frasnelli’s study reveals, said Dr. Hummel.

Also commenting on the research, Kenneth L. Tyler, MD, professor of neurology, University of Colorado at Denver, Aurora, and a fellow of the American Academy of Neurology, said the study was relatively large and the results “interesting.”

Although it “provides more evidence there’s a subset of patients with symptoms even well past the acute phase” of COVID-19, the results are “mostly confirmatory” and include “nothing super surprising,” Dr. Tyler said in an interview.

However, the investigators did attempt to make the study “a little more quantitative” and “to confirm the self-reporting with their validated CD home test,” he said.

Dr. Tyler wondered how representative the sample was and whether the study drew more participants with impaired senses. “If I had a loss of smell or taste, maybe I would be more likely to respond to such a survey,” he said.

He also noted the difficulty of separating loss of smell from loss of taste.

“If you lose your sense of smell, things don’t taste right, so it can be confounding as to how to separate out those two,” he noted.
The study was supported by the Foundation of the Université du Québec à Trois-Rivières and the Province of Quebec. Dr. Frasnelli has received royalties from Styriabooks in Austria for a book on olfaction published in 2019 and has received honoraria for speaking engagements. Dr. Hummel and Dr. Tyler have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

More than 50% of health care workers infected with SARS-CoV-2 report that their sense of smell has not returned to normal an average of 5 months post infection, new research shows.

Nenad Cavoski/iStock/Getty Images Plus

The findings illustrate that olfactory problems are common not only during the acute COVID-19 phase but also “in the long run” and that these problems should be “taken into consideration” when following up these patients, study investigator Johannes Frasnelli, MD, professor, department of anatomy, Université du Québec à Trois-Rivières, said in an interview.

Loss of the sense of smell can affect quality of life because it affects eating and drinking, and may even be dangerous, said Dr. Frasnelli. “If your sense of smell is impaired, you may unknowingly eat spoiled food, or you may not smell smoke or gas in your home,” he said. In addition, Dr. Frasnelli noted that an impaired sense of smell is associated with higher rates of depression. The findings will be presented at the annual meeting of the American Academy of Neurology in April.

‘Striking’ finding

Research shows that about 60% of patients with COVID-19 lose their sense of smell to some degree during the acute phase of the disease. “But we wanted to go further and look at the longer-term effects of loss of smell and taste,” said Dr. Frasnelli.

The analysis included 813 health care workers in the province of Quebec. For all the patients, SARS-CoV-2 infection was confirmed through testing with a nasopharyngeal viral swab.

Participants completed a 64-item online questionnaire that asked about three senses: olfactory; gustatory, which includes tastes such as sweet, sour, bitter, salty, savory and umami; and trigeminal, which includes sensations such as spiciness of hot peppers and “coolness” of mint.

They were asked to rate these on a scale of 0 (no perception) to 10 (very strong perception) before the infection, during the infection, and currently. They were also asked about other symptoms, including fatigue.

Most respondents had been infected in the first wave of the virus in March and April of 2020 and responded to the questionnaire an average of 5 months later.

The vast majority of respondents (84.1%) were women, which Dr. Frasnelli said was not surprising because women predominate in the health care field.

The analysis showed that average smell ratings were 8.98 before infection, 2.85 during the acute phase, and 7.41 when respondents answered the questionnaire. The sense of taste was less affected and recovered faster than did the sense of smell. Results for taste were 9.20 before infection, 3.59 during the acute phase, and 8.05 after COVID-19.

Among 580 respondents who indicated a compromised sense of smell during the acute phase, the average smell rating when answering the questionnaire was 6.89, compared to 9.03 before the infection. More than half (51.2%) reported not regaining full olfactory function.

The fact that the sense of smell had not returned to normal for half the participants so long after being infected is “novel and quite striking,” said Dr. Frasnelli.

However, he noted, this doesn’t necessarily mean all those with a compromised sense of smell “have huge problems.” In some cases, he said, the problem “is more subtle.”
 

Not a CNS problem?

Respondents also completed a chemosensory dysfunction home test (CD-HT). They were asked to prepare common household food items, such as peanut butter, sugar, salt, and vinegar, in a particular way – for example, to add sugar or salt to water – and provide feedback on how they smell and taste.

For this CD-HT analysis, 18.4% of respondents reported having persistent loss of smell. This, Dr. Frasnelli said, adds to evidence from self-reported responses and suggests that in some cases, the problem is more than senses not returning to normal.

“From the questionnaires, roughly 50% said their sense of smell is still not back to normal, and when we look at the CD home test, we see that almost 20% of subjects indeed have pretty strong impairment of their sense of smell,” he said.

The results showed no sex differences, although Dr. Frasnelli noted that most of the sample were women. “It’s tricky to look at the data with regard to sex because it’s a bit skewed,” he said.

Male respondents were older than female participants, but there was no difference in impairment between age groups. Dr. Frasnelli said this was “quite interesting,” inasmuch as older people usually lose some sense of smell.

The researchers have not yet examined whether the results differ by type of health care worker.

They also have not examined in detail whether infection severity affects the risk for extended olfactory impairment. Although some research suggests that the problem with smell is more common in less severe cases, Dr. Frasnelli noted this could be because loss of smell is not a huge problem for patients battling grave health problems.

As for other symptoms, many respondents reported lingering fatigue; some reported debilitating fatigue, said Dr. Frasnelli. However, he cautioned that this is difficult to interpret, because the participants were health care workers, many of whom returned to work during the pandemic and perhaps had not fully rested.

He also noted that he and his colleagues have not “made the link” between impaired smell and the degree of fatigue.

The COVID-19 virus appears to attack supporting sustentacular cells in the olfactory epithelium, not nerve cells.

“Right now, it seems that the smell problem is not a central nervous system problem but a peripheral problem,” said Dr. Frasnelli. “But we don’t know for sure; it may be that the virus somehow gets into the brain and some symptoms are caused by the effects of the infection on the brain.”

The researchers will extend their research with another questionnaire to assess senses 10-12 months after COVID-19.

Limitations of the study include the subjective nature of the smell and taste ratings and the single time point at which data were collected.
 

Confirmatory findings

Commenting on the research in an interview, Thomas Hummel, MD, professor, smell and taste clinic, department of otorhinolaryngology, Technische Universität Dresden (Germany), said the new results regarding loss of smell after COVID-19 are “very congruent” with what he and his colleagues have observed.

Research shows that up to one in five of those infected with SARS-CoV-2 experience olfactory loss. “While the numbers may vary a bit from study to study or lab to lab, I think 5% to 20% of post–COVID-19 patients exhibit long-term olfactory loss,” Dr. Hummel said.

His group has observed that “many more are not back to normal,” which conforms with what Dr. Frasnelli’s study reveals, said Dr. Hummel.

Also commenting on the research, Kenneth L. Tyler, MD, professor of neurology, University of Colorado at Denver, Aurora, and a fellow of the American Academy of Neurology, said the study was relatively large and the results “interesting.”

Although it “provides more evidence there’s a subset of patients with symptoms even well past the acute phase” of COVID-19, the results are “mostly confirmatory” and include “nothing super surprising,” Dr. Tyler said in an interview.

However, the investigators did attempt to make the study “a little more quantitative” and “to confirm the self-reporting with their validated CD home test,” he said.

Dr. Tyler wondered how representative the sample was and whether the study drew more participants with impaired senses. “If I had a loss of smell or taste, maybe I would be more likely to respond to such a survey,” he said.

He also noted the difficulty of separating loss of smell from loss of taste.

“If you lose your sense of smell, things don’t taste right, so it can be confounding as to how to separate out those two,” he noted.
The study was supported by the Foundation of the Université du Québec à Trois-Rivières and the Province of Quebec. Dr. Frasnelli has received royalties from Styriabooks in Austria for a book on olfaction published in 2019 and has received honoraria for speaking engagements. Dr. Hummel and Dr. Tyler have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

More than 50% of health care workers infected with SARS-CoV-2 report that their sense of smell has not returned to normal an average of 5 months post infection, new research shows.

Nenad Cavoski/iStock/Getty Images Plus

The findings illustrate that olfactory problems are common not only during the acute COVID-19 phase but also “in the long run” and that these problems should be “taken into consideration” when following up these patients, study investigator Johannes Frasnelli, MD, professor, department of anatomy, Université du Québec à Trois-Rivières, said in an interview.

Loss of the sense of smell can affect quality of life because it affects eating and drinking, and may even be dangerous, said Dr. Frasnelli. “If your sense of smell is impaired, you may unknowingly eat spoiled food, or you may not smell smoke or gas in your home,” he said. In addition, Dr. Frasnelli noted that an impaired sense of smell is associated with higher rates of depression. The findings will be presented at the annual meeting of the American Academy of Neurology in April.

‘Striking’ finding

Research shows that about 60% of patients with COVID-19 lose their sense of smell to some degree during the acute phase of the disease. “But we wanted to go further and look at the longer-term effects of loss of smell and taste,” said Dr. Frasnelli.

The analysis included 813 health care workers in the province of Quebec. For all the patients, SARS-CoV-2 infection was confirmed through testing with a nasopharyngeal viral swab.

Participants completed a 64-item online questionnaire that asked about three senses: olfactory; gustatory, which includes tastes such as sweet, sour, bitter, salty, savory and umami; and trigeminal, which includes sensations such as spiciness of hot peppers and “coolness” of mint.

They were asked to rate these on a scale of 0 (no perception) to 10 (very strong perception) before the infection, during the infection, and currently. They were also asked about other symptoms, including fatigue.

Most respondents had been infected in the first wave of the virus in March and April of 2020 and responded to the questionnaire an average of 5 months later.

The vast majority of respondents (84.1%) were women, which Dr. Frasnelli said was not surprising because women predominate in the health care field.

The analysis showed that average smell ratings were 8.98 before infection, 2.85 during the acute phase, and 7.41 when respondents answered the questionnaire. The sense of taste was less affected and recovered faster than did the sense of smell. Results for taste were 9.20 before infection, 3.59 during the acute phase, and 8.05 after COVID-19.

Among 580 respondents who indicated a compromised sense of smell during the acute phase, the average smell rating when answering the questionnaire was 6.89, compared to 9.03 before the infection. More than half (51.2%) reported not regaining full olfactory function.

The fact that the sense of smell had not returned to normal for half the participants so long after being infected is “novel and quite striking,” said Dr. Frasnelli.

However, he noted, this doesn’t necessarily mean all those with a compromised sense of smell “have huge problems.” In some cases, he said, the problem “is more subtle.”
 

Not a CNS problem?

Respondents also completed a chemosensory dysfunction home test (CD-HT). They were asked to prepare common household food items, such as peanut butter, sugar, salt, and vinegar, in a particular way – for example, to add sugar or salt to water – and provide feedback on how they smell and taste.

For this CD-HT analysis, 18.4% of respondents reported having persistent loss of smell. This, Dr. Frasnelli said, adds to evidence from self-reported responses and suggests that in some cases, the problem is more than senses not returning to normal.

“From the questionnaires, roughly 50% said their sense of smell is still not back to normal, and when we look at the CD home test, we see that almost 20% of subjects indeed have pretty strong impairment of their sense of smell,” he said.

The results showed no sex differences, although Dr. Frasnelli noted that most of the sample were women. “It’s tricky to look at the data with regard to sex because it’s a bit skewed,” he said.

Male respondents were older than female participants, but there was no difference in impairment between age groups. Dr. Frasnelli said this was “quite interesting,” inasmuch as older people usually lose some sense of smell.

The researchers have not yet examined whether the results differ by type of health care worker.

They also have not examined in detail whether infection severity affects the risk for extended olfactory impairment. Although some research suggests that the problem with smell is more common in less severe cases, Dr. Frasnelli noted this could be because loss of smell is not a huge problem for patients battling grave health problems.

As for other symptoms, many respondents reported lingering fatigue; some reported debilitating fatigue, said Dr. Frasnelli. However, he cautioned that this is difficult to interpret, because the participants were health care workers, many of whom returned to work during the pandemic and perhaps had not fully rested.

He also noted that he and his colleagues have not “made the link” between impaired smell and the degree of fatigue.

The COVID-19 virus appears to attack supporting sustentacular cells in the olfactory epithelium, not nerve cells.

“Right now, it seems that the smell problem is not a central nervous system problem but a peripheral problem,” said Dr. Frasnelli. “But we don’t know for sure; it may be that the virus somehow gets into the brain and some symptoms are caused by the effects of the infection on the brain.”

The researchers will extend their research with another questionnaire to assess senses 10-12 months after COVID-19.

Limitations of the study include the subjective nature of the smell and taste ratings and the single time point at which data were collected.
 

Confirmatory findings

Commenting on the research in an interview, Thomas Hummel, MD, professor, smell and taste clinic, department of otorhinolaryngology, Technische Universität Dresden (Germany), said the new results regarding loss of smell after COVID-19 are “very congruent” with what he and his colleagues have observed.

Research shows that up to one in five of those infected with SARS-CoV-2 experience olfactory loss. “While the numbers may vary a bit from study to study or lab to lab, I think 5% to 20% of post–COVID-19 patients exhibit long-term olfactory loss,” Dr. Hummel said.

His group has observed that “many more are not back to normal,” which conforms with what Dr. Frasnelli’s study reveals, said Dr. Hummel.

Also commenting on the research, Kenneth L. Tyler, MD, professor of neurology, University of Colorado at Denver, Aurora, and a fellow of the American Academy of Neurology, said the study was relatively large and the results “interesting.”

Although it “provides more evidence there’s a subset of patients with symptoms even well past the acute phase” of COVID-19, the results are “mostly confirmatory” and include “nothing super surprising,” Dr. Tyler said in an interview.

However, the investigators did attempt to make the study “a little more quantitative” and “to confirm the self-reporting with their validated CD home test,” he said.

Dr. Tyler wondered how representative the sample was and whether the study drew more participants with impaired senses. “If I had a loss of smell or taste, maybe I would be more likely to respond to such a survey,” he said.

He also noted the difficulty of separating loss of smell from loss of taste.

“If you lose your sense of smell, things don’t taste right, so it can be confounding as to how to separate out those two,” he noted.
The study was supported by the Foundation of the Université du Québec à Trois-Rivières and the Province of Quebec. Dr. Frasnelli has received royalties from Styriabooks in Austria for a book on olfaction published in 2019 and has received honoraria for speaking engagements. Dr. Hummel and Dr. Tyler have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

More than half of respondents to a recent survey looking at how the COVID-19 pandemic has affected people with psoriasis or psoriatic arthritis (PsA) said that they had avoided seeking medical care in person with a doctor or at a hospital.

Courtesy National Psoriasis Foundation

Moreover, around a quarter had their appointment with a rheumatologist canceled, rescheduled, or conducted virtually. Another 1 in 10 had their treatment plan disrupted, and 6% had to change or stop treatment entirely.

The mental health impact of living with these conditions during the pandemic was also notable, said Rachael Manion, the executive director of the Canadian Association of Psoriasis Patients (CAPP), which conducted the survey in collaboration with the Canadian Psoriasis Network (CPN) and Unmasking Psoriasis.

“It’s important to know that there have been a lot of different impacts of the pandemic on people living with psoriatic arthritis and psoriasis. Mental health in particular has had a really big hit as a result,” she said at the Canadian Arthritis Research Conference: Research with Impact.

“About half of the people who responded to our survey noted that their mental health was ‘worse’ or ‘much worse’ during the pandemic,” she said at the meeting, which was sponsored by the Arthritis Society, the Canadian Rheumatology Association, and Canada’s Institute of Musculoskeletal Health and Arthritis. Anxiety and feelings of isolation were reported by a respective 57% and 58% of respondents, and 40% reported depression.

“We can compare that to our earlier information around depression,” Ms. Manion said, which showed that, prior to the pandemic, 24% of people with psoriasis and 23% of those with PsA had said they experienced depression.

“What I found alarming looking at these results was that about a third of people were experiencing despair. Now that’s a really big, scary, overwhelming emotion that has a lot of burden on your mental health,” Ms. Manion said.

Despite the substantial effects on mental health, only 29% of respondents said they had been able to access mental health services during the pandemic.

To look at the impact of the COVID-19 pandemic on the psoriasis and PsA community in Canada, three patient advocacy groups – CAPP, CPN, and Unmasking Psoriasis – codeveloped a survey to look at the disease experience before and after the start of the COVID-19 pandemic. The survey was performed once, with 830 respondents providing information on their lives with psoriasis or PsA in the months before the start of the pandemic and at the time they were surveyed in September and October 2020.

Most of the survey respondents lived in Ontario, Quebec, British Columbia, or Alberta, although other provinces or territories were represented. Almost all respondents (96%) had psoriasis, and 60% also had PsA.

Pre-COVID, nearly half (49%) of patients said that they had not been seen by a rheumatologist, and 39% had not seen a dermatologist for treatment. Asked why, 56% and 27%, respectively, had not been referred, 9% and 15% said they had no specialist located nearby, and 7% and 10% stated that the wait list was too long.

“This tells us that there’s a lot more work that can be done and a lot more education of general practitioners and family medicine professionals about the benefits and the value of specialized care for psoriatic arthritis,” Ms. Manion suggested.

Before the pandemic, joint pain was occurring in 88% of patients, stiffness in 71%, and joint swelling in 67%. Disease flares or sudden periods of worsening occurred on a daily basis for 17%, and around one in five (21%) experienced multiple flares every month.

Prepandemic data also highlighted the negative impact that living with psoriasis or PsA has on people’s ability to sleep, interactions and intimacy with others, and on their school or work lives.

During the pandemic, around a quarter (26%) of respondents said they had worse or much worse access to employment, as well as its benefits such as a stable income (24%). A minority of respondent also described worse access to prescription medication (15%) and over-the-counter medication (13%).

“There are all kinds of things going on for patients in our community: changes to their work, changes to their drug coverage, their ability to sleep and sleep well, their mental health, and their ability to access care and treatments as part of their disease management,” Ms. Manion said.

Her final message to health care professionals was: “I just want to encourage you to continue to check in with your patients about what their experiences have been during the pandemic, and to really consider those impacts as you’re working with them to manage their disease.”

The survey received funding support from AbbVie, Bausch Health, Boehringer Ingelheim, Janssen, LEO Pharma, and Novartis.

More than half of respondents to a recent survey looking at how the COVID-19 pandemic has affected people with psoriasis or psoriatic arthritis (PsA) said that they had avoided seeking medical care in person with a doctor or at a hospital.

Courtesy National Psoriasis Foundation

Moreover, around a quarter had their appointment with a rheumatologist canceled, rescheduled, or conducted virtually. Another 1 in 10 had their treatment plan disrupted, and 6% had to change or stop treatment entirely.

The mental health impact of living with these conditions during the pandemic was also notable, said Rachael Manion, the executive director of the Canadian Association of Psoriasis Patients (CAPP), which conducted the survey in collaboration with the Canadian Psoriasis Network (CPN) and Unmasking Psoriasis.

“It’s important to know that there have been a lot of different impacts of the pandemic on people living with psoriatic arthritis and psoriasis. Mental health in particular has had a really big hit as a result,” she said at the Canadian Arthritis Research Conference: Research with Impact.

“About half of the people who responded to our survey noted that their mental health was ‘worse’ or ‘much worse’ during the pandemic,” she said at the meeting, which was sponsored by the Arthritis Society, the Canadian Rheumatology Association, and Canada’s Institute of Musculoskeletal Health and Arthritis. Anxiety and feelings of isolation were reported by a respective 57% and 58% of respondents, and 40% reported depression.

“We can compare that to our earlier information around depression,” Ms. Manion said, which showed that, prior to the pandemic, 24% of people with psoriasis and 23% of those with PsA had said they experienced depression.

“What I found alarming looking at these results was that about a third of people were experiencing despair. Now that’s a really big, scary, overwhelming emotion that has a lot of burden on your mental health,” Ms. Manion said.

Despite the substantial effects on mental health, only 29% of respondents said they had been able to access mental health services during the pandemic.

To look at the impact of the COVID-19 pandemic on the psoriasis and PsA community in Canada, three patient advocacy groups – CAPP, CPN, and Unmasking Psoriasis – codeveloped a survey to look at the disease experience before and after the start of the COVID-19 pandemic. The survey was performed once, with 830 respondents providing information on their lives with psoriasis or PsA in the months before the start of the pandemic and at the time they were surveyed in September and October 2020.

Most of the survey respondents lived in Ontario, Quebec, British Columbia, or Alberta, although other provinces or territories were represented. Almost all respondents (96%) had psoriasis, and 60% also had PsA.

Pre-COVID, nearly half (49%) of patients said that they had not been seen by a rheumatologist, and 39% had not seen a dermatologist for treatment. Asked why, 56% and 27%, respectively, had not been referred, 9% and 15% said they had no specialist located nearby, and 7% and 10% stated that the wait list was too long.

“This tells us that there’s a lot more work that can be done and a lot more education of general practitioners and family medicine professionals about the benefits and the value of specialized care for psoriatic arthritis,” Ms. Manion suggested.

Before the pandemic, joint pain was occurring in 88% of patients, stiffness in 71%, and joint swelling in 67%. Disease flares or sudden periods of worsening occurred on a daily basis for 17%, and around one in five (21%) experienced multiple flares every month.

Prepandemic data also highlighted the negative impact that living with psoriasis or PsA has on people’s ability to sleep, interactions and intimacy with others, and on their school or work lives.

During the pandemic, around a quarter (26%) of respondents said they had worse or much worse access to employment, as well as its benefits such as a stable income (24%). A minority of respondent also described worse access to prescription medication (15%) and over-the-counter medication (13%).

“There are all kinds of things going on for patients in our community: changes to their work, changes to their drug coverage, their ability to sleep and sleep well, their mental health, and their ability to access care and treatments as part of their disease management,” Ms. Manion said.

Her final message to health care professionals was: “I just want to encourage you to continue to check in with your patients about what their experiences have been during the pandemic, and to really consider those impacts as you’re working with them to manage their disease.”

The survey received funding support from AbbVie, Bausch Health, Boehringer Ingelheim, Janssen, LEO Pharma, and Novartis.

More than half of respondents to a recent survey looking at how the COVID-19 pandemic has affected people with psoriasis or psoriatic arthritis (PsA) said that they had avoided seeking medical care in person with a doctor or at a hospital.

Courtesy National Psoriasis Foundation

Moreover, around a quarter had their appointment with a rheumatologist canceled, rescheduled, or conducted virtually. Another 1 in 10 had their treatment plan disrupted, and 6% had to change or stop treatment entirely.

The mental health impact of living with these conditions during the pandemic was also notable, said Rachael Manion, the executive director of the Canadian Association of Psoriasis Patients (CAPP), which conducted the survey in collaboration with the Canadian Psoriasis Network (CPN) and Unmasking Psoriasis.

“It’s important to know that there have been a lot of different impacts of the pandemic on people living with psoriatic arthritis and psoriasis. Mental health in particular has had a really big hit as a result,” she said at the Canadian Arthritis Research Conference: Research with Impact.

“About half of the people who responded to our survey noted that their mental health was ‘worse’ or ‘much worse’ during the pandemic,” she said at the meeting, which was sponsored by the Arthritis Society, the Canadian Rheumatology Association, and Canada’s Institute of Musculoskeletal Health and Arthritis. Anxiety and feelings of isolation were reported by a respective 57% and 58% of respondents, and 40% reported depression.

“We can compare that to our earlier information around depression,” Ms. Manion said, which showed that, prior to the pandemic, 24% of people with psoriasis and 23% of those with PsA had said they experienced depression.

“What I found alarming looking at these results was that about a third of people were experiencing despair. Now that’s a really big, scary, overwhelming emotion that has a lot of burden on your mental health,” Ms. Manion said.

Despite the substantial effects on mental health, only 29% of respondents said they had been able to access mental health services during the pandemic.

To look at the impact of the COVID-19 pandemic on the psoriasis and PsA community in Canada, three patient advocacy groups – CAPP, CPN, and Unmasking Psoriasis – codeveloped a survey to look at the disease experience before and after the start of the COVID-19 pandemic. The survey was performed once, with 830 respondents providing information on their lives with psoriasis or PsA in the months before the start of the pandemic and at the time they were surveyed in September and October 2020.

Most of the survey respondents lived in Ontario, Quebec, British Columbia, or Alberta, although other provinces or territories were represented. Almost all respondents (96%) had psoriasis, and 60% also had PsA.

Pre-COVID, nearly half (49%) of patients said that they had not been seen by a rheumatologist, and 39% had not seen a dermatologist for treatment. Asked why, 56% and 27%, respectively, had not been referred, 9% and 15% said they had no specialist located nearby, and 7% and 10% stated that the wait list was too long.

“This tells us that there’s a lot more work that can be done and a lot more education of general practitioners and family medicine professionals about the benefits and the value of specialized care for psoriatic arthritis,” Ms. Manion suggested.

Before the pandemic, joint pain was occurring in 88% of patients, stiffness in 71%, and joint swelling in 67%. Disease flares or sudden periods of worsening occurred on a daily basis for 17%, and around one in five (21%) experienced multiple flares every month.

Prepandemic data also highlighted the negative impact that living with psoriasis or PsA has on people’s ability to sleep, interactions and intimacy with others, and on their school or work lives.

During the pandemic, around a quarter (26%) of respondents said they had worse or much worse access to employment, as well as its benefits such as a stable income (24%). A minority of respondent also described worse access to prescription medication (15%) and over-the-counter medication (13%).

“There are all kinds of things going on for patients in our community: changes to their work, changes to their drug coverage, their ability to sleep and sleep well, their mental health, and their ability to access care and treatments as part of their disease management,” Ms. Manion said.

Her final message to health care professionals was: “I just want to encourage you to continue to check in with your patients about what their experiences have been during the pandemic, and to really consider those impacts as you’re working with them to manage their disease.”

The survey received funding support from AbbVie, Bausch Health, Boehringer Ingelheim, Janssen, LEO Pharma, and Novartis.

A novel T-cell engineered product, Orca-T (Orca Bio), was associated with lower incidence of both acute and chronic graft-versus-host disease (GVHD) and more than double the rate of GVHD-free and relapse-free survival, compared with the current standard of care for patients undergoing hematopoietic stem cell transplants (HSCT), investigators said.

In both a multicenter phase 1 trial (NCT04013685) and single-center phase 1/2 trial (NCT01660607) with a total of 50 patients, those who received Orca-T with single-agent GVHD prophylaxis had a 1-year GVHD-free and relapse-free survival rate of 75%, compared with 31% for patients who received standard of care with two-agent prophylaxis, reported Everett H. Meyer, MD, PhD, from the Stanford (Calif.) University.

“Orca-T has good evidence for reduced acute graft-versus-host disease, reduced chromic graft-versus-host disease, and a low nonrelapse mortality,” he said at the Transplant & Cellular Therapies Meetings.

The product can be quickly manufactured and delivered to treatment centers across the continental United States, with “vein-to-vein” time of less than 72 hours, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Orca-T consists of highly purified, donor-derived T-regulatory (Treg) cells that are sorted and delivered on day 0 with hematopoietic stem cells, without immunosuppressants, followed 2 days later with infusion of a matching dose of conventional T cells.

“The Treg cells are allowed to expand to create the right microenvironment for the [conventional T cells],” he explained.

In preclinical studies, donor-derived, high-purity Tregs delivered prior to adoptive transfer of conventional T cells prevented GVHD while maintaining graft-versus-tumor immunity, he said.
 

Two T-cell infusions

He reported updated results from current studies on a total of 50 adults, with a cohort of 144 patients treated concurrently with standard of care as controls.

The Orca-T–treated patients had a median age of 47 and 52% were male. Indications for transplant included acute myeloid and acute lymphoblastic leukemia, chronic myeloid leukemia, B-cell lymphoma, myelodysplastic syndrome/myelofibrosis, and other unspecified indications.

In both the Orca-T and control cohorts, patients underwent myeloablative conditioning from 10 to 2 days prior to stem cell infusion.

As noted patients in the experimental arm received infusion of hematopoietic stem/progenitor cells and Tregs, followed 2 days later by conventional T-cell infusion, and, on the day after that, tacrolimus at a target dose of 4.6 ng/mL. The conventional T cells were reserved from donor apheresis and were otherwise unmanipulated prior to infusion into the recipient, Dr. Meyer noted.

Patients in the standard-of-care arm received tacrolimus on the day before standard infusion of the apheresis product, followed by methotrexate prophylaxis on days 1, 3, 6 and 11.

Time to neutrophil engraftment, platelet engraftment, and from day 0 to hospital discharge were all significantly shorter in the Orca-T group, at 12 versus 14 days (P < .0001), 11 vs. 17 days (P < .0001), and 15 vs. 17 days (P = .01) respectively.

At 100 days of follow-up, the rate of grade 2 or greater acute GVHD was 30% among standard-of-care patients versus 10% among Orca-T–treated patients. At 1-year follow-up, respective rates of chronic GVHD were 46% vs. 3%.
 

Safety

“In general, the protocol is extremely well tolerated by our patients. We’ve seen no exceptional infectious disease complications, and we’ve seen no other major complications,” Dr. Meyer said.

Cytomegalovirus prophylaxis was used variably, depending on the center and on the attending physician. Epstein-Barr virus reactivation occurred in eight patients, with one requiring therapy, but there was no biopsy or radiographic evidence of posttransplant lymphoproliferative disorder.

In all, 18% of patients had serious adverse events during the reporting period, all of which resolved. There were no treatment-related deaths in the Orca-T arm, compared with 11% of controls.
 

Engraftment differences explored

In the question-and-answer session following the presentation, Christopher J. Gamper, MD, PhD, from the Johns Hopkins Hospital in Baltimore, told Dr. Meyer that “your outcomes from Orca-T look excellent,” and asked about the cost differential, compared with similar, unmanipulated transplants performed with standard GVHD prophylaxis.

“Is this recovered by lower costs for treatment of GVHD?” he asked.

“I have not done an economic cost analysis of course, and I think others may be looking into this,” Dr. Meyer replied. “Graft engineering can be expensive, although it’s an engineering proposition and one could imagine that the costs will go down substantially over time.”

Session moderator Alan Hanash, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York, commented on the differences in engraftment between the experimental controls arms, and asked Dr. Meyer: “Do you think this is due to the difference in prophylaxis? Absence of methotrexate? Do you think that it could be a direct impact of regulatory T cells on hematopoietic engraftment?”

“Certainly not having methotrexate is beneficial for engraftment, and may account for the differences we see, Dr. Meyer said. “However, it is possible that Tregs could be playing a facilitative role. There certainly is good preclinical literature that Tregs, particularly in the bone marrow space, can facilitate bone marrow engraftment.”

The Orca-T trials are sponsored by Orca Bio and Stanford, with support from the National Institutes of Health. Dr. Meyer receives research support from Orca and is a scientific adviser to GigaGen, Triursus, Incyte, and Indee Labs. Dr. Hanash and Dr. Gamper had no relevant disclosures.

A novel T-cell engineered product, Orca-T (Orca Bio), was associated with lower incidence of both acute and chronic graft-versus-host disease (GVHD) and more than double the rate of GVHD-free and relapse-free survival, compared with the current standard of care for patients undergoing hematopoietic stem cell transplants (HSCT), investigators said.

In both a multicenter phase 1 trial (NCT04013685) and single-center phase 1/2 trial (NCT01660607) with a total of 50 patients, those who received Orca-T with single-agent GVHD prophylaxis had a 1-year GVHD-free and relapse-free survival rate of 75%, compared with 31% for patients who received standard of care with two-agent prophylaxis, reported Everett H. Meyer, MD, PhD, from the Stanford (Calif.) University.

“Orca-T has good evidence for reduced acute graft-versus-host disease, reduced chromic graft-versus-host disease, and a low nonrelapse mortality,” he said at the Transplant & Cellular Therapies Meetings.

The product can be quickly manufactured and delivered to treatment centers across the continental United States, with “vein-to-vein” time of less than 72 hours, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Orca-T consists of highly purified, donor-derived T-regulatory (Treg) cells that are sorted and delivered on day 0 with hematopoietic stem cells, without immunosuppressants, followed 2 days later with infusion of a matching dose of conventional T cells.

“The Treg cells are allowed to expand to create the right microenvironment for the [conventional T cells],” he explained.

In preclinical studies, donor-derived, high-purity Tregs delivered prior to adoptive transfer of conventional T cells prevented GVHD while maintaining graft-versus-tumor immunity, he said.
 

Two T-cell infusions

He reported updated results from current studies on a total of 50 adults, with a cohort of 144 patients treated concurrently with standard of care as controls.

The Orca-T–treated patients had a median age of 47 and 52% were male. Indications for transplant included acute myeloid and acute lymphoblastic leukemia, chronic myeloid leukemia, B-cell lymphoma, myelodysplastic syndrome/myelofibrosis, and other unspecified indications.

In both the Orca-T and control cohorts, patients underwent myeloablative conditioning from 10 to 2 days prior to stem cell infusion.

As noted patients in the experimental arm received infusion of hematopoietic stem/progenitor cells and Tregs, followed 2 days later by conventional T-cell infusion, and, on the day after that, tacrolimus at a target dose of 4.6 ng/mL. The conventional T cells were reserved from donor apheresis and were otherwise unmanipulated prior to infusion into the recipient, Dr. Meyer noted.

Patients in the standard-of-care arm received tacrolimus on the day before standard infusion of the apheresis product, followed by methotrexate prophylaxis on days 1, 3, 6 and 11.

Time to neutrophil engraftment, platelet engraftment, and from day 0 to hospital discharge were all significantly shorter in the Orca-T group, at 12 versus 14 days (P < .0001), 11 vs. 17 days (P < .0001), and 15 vs. 17 days (P = .01) respectively.

At 100 days of follow-up, the rate of grade 2 or greater acute GVHD was 30% among standard-of-care patients versus 10% among Orca-T–treated patients. At 1-year follow-up, respective rates of chronic GVHD were 46% vs. 3%.
 

Safety

“In general, the protocol is extremely well tolerated by our patients. We’ve seen no exceptional infectious disease complications, and we’ve seen no other major complications,” Dr. Meyer said.

Cytomegalovirus prophylaxis was used variably, depending on the center and on the attending physician. Epstein-Barr virus reactivation occurred in eight patients, with one requiring therapy, but there was no biopsy or radiographic evidence of posttransplant lymphoproliferative disorder.

In all, 18% of patients had serious adverse events during the reporting period, all of which resolved. There were no treatment-related deaths in the Orca-T arm, compared with 11% of controls.
 

Engraftment differences explored

In the question-and-answer session following the presentation, Christopher J. Gamper, MD, PhD, from the Johns Hopkins Hospital in Baltimore, told Dr. Meyer that “your outcomes from Orca-T look excellent,” and asked about the cost differential, compared with similar, unmanipulated transplants performed with standard GVHD prophylaxis.

“Is this recovered by lower costs for treatment of GVHD?” he asked.

“I have not done an economic cost analysis of course, and I think others may be looking into this,” Dr. Meyer replied. “Graft engineering can be expensive, although it’s an engineering proposition and one could imagine that the costs will go down substantially over time.”

Session moderator Alan Hanash, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York, commented on the differences in engraftment between the experimental controls arms, and asked Dr. Meyer: “Do you think this is due to the difference in prophylaxis? Absence of methotrexate? Do you think that it could be a direct impact of regulatory T cells on hematopoietic engraftment?”

“Certainly not having methotrexate is beneficial for engraftment, and may account for the differences we see, Dr. Meyer said. “However, it is possible that Tregs could be playing a facilitative role. There certainly is good preclinical literature that Tregs, particularly in the bone marrow space, can facilitate bone marrow engraftment.”

The Orca-T trials are sponsored by Orca Bio and Stanford, with support from the National Institutes of Health. Dr. Meyer receives research support from Orca and is a scientific adviser to GigaGen, Triursus, Incyte, and Indee Labs. Dr. Hanash and Dr. Gamper had no relevant disclosures.

A novel T-cell engineered product, Orca-T (Orca Bio), was associated with lower incidence of both acute and chronic graft-versus-host disease (GVHD) and more than double the rate of GVHD-free and relapse-free survival, compared with the current standard of care for patients undergoing hematopoietic stem cell transplants (HSCT), investigators said.

In both a multicenter phase 1 trial (NCT04013685) and single-center phase 1/2 trial (NCT01660607) with a total of 50 patients, those who received Orca-T with single-agent GVHD prophylaxis had a 1-year GVHD-free and relapse-free survival rate of 75%, compared with 31% for patients who received standard of care with two-agent prophylaxis, reported Everett H. Meyer, MD, PhD, from the Stanford (Calif.) University.

“Orca-T has good evidence for reduced acute graft-versus-host disease, reduced chromic graft-versus-host disease, and a low nonrelapse mortality,” he said at the Transplant & Cellular Therapies Meetings.

The product can be quickly manufactured and delivered to treatment centers across the continental United States, with “vein-to-vein” time of less than 72 hours, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Orca-T consists of highly purified, donor-derived T-regulatory (Treg) cells that are sorted and delivered on day 0 with hematopoietic stem cells, without immunosuppressants, followed 2 days later with infusion of a matching dose of conventional T cells.

“The Treg cells are allowed to expand to create the right microenvironment for the [conventional T cells],” he explained.

In preclinical studies, donor-derived, high-purity Tregs delivered prior to adoptive transfer of conventional T cells prevented GVHD while maintaining graft-versus-tumor immunity, he said.
 

Two T-cell infusions

He reported updated results from current studies on a total of 50 adults, with a cohort of 144 patients treated concurrently with standard of care as controls.

The Orca-T–treated patients had a median age of 47 and 52% were male. Indications for transplant included acute myeloid and acute lymphoblastic leukemia, chronic myeloid leukemia, B-cell lymphoma, myelodysplastic syndrome/myelofibrosis, and other unspecified indications.

In both the Orca-T and control cohorts, patients underwent myeloablative conditioning from 10 to 2 days prior to stem cell infusion.

As noted patients in the experimental arm received infusion of hematopoietic stem/progenitor cells and Tregs, followed 2 days later by conventional T-cell infusion, and, on the day after that, tacrolimus at a target dose of 4.6 ng/mL. The conventional T cells were reserved from donor apheresis and were otherwise unmanipulated prior to infusion into the recipient, Dr. Meyer noted.

Patients in the standard-of-care arm received tacrolimus on the day before standard infusion of the apheresis product, followed by methotrexate prophylaxis on days 1, 3, 6 and 11.

Time to neutrophil engraftment, platelet engraftment, and from day 0 to hospital discharge were all significantly shorter in the Orca-T group, at 12 versus 14 days (P < .0001), 11 vs. 17 days (P < .0001), and 15 vs. 17 days (P = .01) respectively.

At 100 days of follow-up, the rate of grade 2 or greater acute GVHD was 30% among standard-of-care patients versus 10% among Orca-T–treated patients. At 1-year follow-up, respective rates of chronic GVHD were 46% vs. 3%.
 

Safety

“In general, the protocol is extremely well tolerated by our patients. We’ve seen no exceptional infectious disease complications, and we’ve seen no other major complications,” Dr. Meyer said.

Cytomegalovirus prophylaxis was used variably, depending on the center and on the attending physician. Epstein-Barr virus reactivation occurred in eight patients, with one requiring therapy, but there was no biopsy or radiographic evidence of posttransplant lymphoproliferative disorder.

In all, 18% of patients had serious adverse events during the reporting period, all of which resolved. There were no treatment-related deaths in the Orca-T arm, compared with 11% of controls.
 

Engraftment differences explored

In the question-and-answer session following the presentation, Christopher J. Gamper, MD, PhD, from the Johns Hopkins Hospital in Baltimore, told Dr. Meyer that “your outcomes from Orca-T look excellent,” and asked about the cost differential, compared with similar, unmanipulated transplants performed with standard GVHD prophylaxis.

“Is this recovered by lower costs for treatment of GVHD?” he asked.

“I have not done an economic cost analysis of course, and I think others may be looking into this,” Dr. Meyer replied. “Graft engineering can be expensive, although it’s an engineering proposition and one could imagine that the costs will go down substantially over time.”

Session moderator Alan Hanash, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York, commented on the differences in engraftment between the experimental controls arms, and asked Dr. Meyer: “Do you think this is due to the difference in prophylaxis? Absence of methotrexate? Do you think that it could be a direct impact of regulatory T cells on hematopoietic engraftment?”

“Certainly not having methotrexate is beneficial for engraftment, and may account for the differences we see, Dr. Meyer said. “However, it is possible that Tregs could be playing a facilitative role. There certainly is good preclinical literature that Tregs, particularly in the bone marrow space, can facilitate bone marrow engraftment.”

The Orca-T trials are sponsored by Orca Bio and Stanford, with support from the National Institutes of Health. Dr. Meyer receives research support from Orca and is a scientific adviser to GigaGen, Triursus, Incyte, and Indee Labs. Dr. Hanash and Dr. Gamper had no relevant disclosures.