Contrary to prior reports, certolizumab pegol may not be associated with an increased risk of serious infections versus other biologics used in the treatment of rheumatoid arthritis, according to results of a recent U.K. registry study.

Certolizumab pegol (Cimzia) actually had a lower risk of serious infections, compared with etanercept in the primary analysis, according to a report on the study recently published in Annals of the Rheumatic Diseases.

In sensitivity analyses, though, the result in favor of certolizumab pegol was no longer significant, according to lead author Andrew I. Rutherford, MBBS, of King’s College London, and his coauthors.

“From these results, it would be wrong to conclude that certolizumab pegol has a lower rate of [serious infection] than other biologics,” Dr. Rutherford and his colleagues said in their report. “However, the risk does not appear to be significantly higher as has previously been suggested.”

The prospective, observational cohort study, based on data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA), represented 19,282 patients with 46,771 years of follow-up, according to the authors.

For the entire cohort, the incidence of serious infections was 5.51 cases per 100 patient-years (95% confidence interval, 5.29-5.71), and the 30-day mortality after serious infection was 10.4% (95% CI, 9.2%-11.6%), the report said. Compared with etanercept, the risk of serious infections was lower for certolizumab pegol (adjusted hazard ratio, 0.75; 95% CI, 0.58-0.97). Etanercept was used as the reference arm for comparison since it was the most widely prescribed drug in the registry.

That finding is in “direct contradiction” to a 2011 Cochrane review finding that certolizumab pegol was associated with an infection rate three to four times higher than other anti–tumor necrosis factor (anti-TNF) drugs (Cochrane Database Syst Rev. 2011;2:Cd008794), the authors noted.

SOURCE: Rutherford AI et al. Ann Rheum Dis. 2018 Mar 28. doi: 10.1136/annrheumdis-2017-212825.

Contrary to prior reports, certolizumab pegol may not be associated with an increased risk of serious infections versus other biologics used in the treatment of rheumatoid arthritis, according to results of a recent U.K. registry study.

Certolizumab pegol (Cimzia) actually had a lower risk of serious infections, compared with etanercept in the primary analysis, according to a report on the study recently published in Annals of the Rheumatic Diseases.

In sensitivity analyses, though, the result in favor of certolizumab pegol was no longer significant, according to lead author Andrew I. Rutherford, MBBS, of King’s College London, and his coauthors.

“From these results, it would be wrong to conclude that certolizumab pegol has a lower rate of [serious infection] than other biologics,” Dr. Rutherford and his colleagues said in their report. “However, the risk does not appear to be significantly higher as has previously been suggested.”

The prospective, observational cohort study, based on data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA), represented 19,282 patients with 46,771 years of follow-up, according to the authors.

For the entire cohort, the incidence of serious infections was 5.51 cases per 100 patient-years (95% confidence interval, 5.29-5.71), and the 30-day mortality after serious infection was 10.4% (95% CI, 9.2%-11.6%), the report said. Compared with etanercept, the risk of serious infections was lower for certolizumab pegol (adjusted hazard ratio, 0.75; 95% CI, 0.58-0.97). Etanercept was used as the reference arm for comparison since it was the most widely prescribed drug in the registry.

That finding is in “direct contradiction” to a 2011 Cochrane review finding that certolizumab pegol was associated with an infection rate three to four times higher than other anti–tumor necrosis factor (anti-TNF) drugs (Cochrane Database Syst Rev. 2011;2:Cd008794), the authors noted.

SOURCE: Rutherford AI et al. Ann Rheum Dis. 2018 Mar 28. doi: 10.1136/annrheumdis-2017-212825.

Contrary to prior reports, certolizumab pegol may not be associated with an increased risk of serious infections versus other biologics used in the treatment of rheumatoid arthritis, according to results of a recent U.K. registry study.

Certolizumab pegol (Cimzia) actually had a lower risk of serious infections, compared with etanercept in the primary analysis, according to a report on the study recently published in Annals of the Rheumatic Diseases.

In sensitivity analyses, though, the result in favor of certolizumab pegol was no longer significant, according to lead author Andrew I. Rutherford, MBBS, of King’s College London, and his coauthors.

“From these results, it would be wrong to conclude that certolizumab pegol has a lower rate of [serious infection] than other biologics,” Dr. Rutherford and his colleagues said in their report. “However, the risk does not appear to be significantly higher as has previously been suggested.”

The prospective, observational cohort study, based on data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA), represented 19,282 patients with 46,771 years of follow-up, according to the authors.

For the entire cohort, the incidence of serious infections was 5.51 cases per 100 patient-years (95% confidence interval, 5.29-5.71), and the 30-day mortality after serious infection was 10.4% (95% CI, 9.2%-11.6%), the report said. Compared with etanercept, the risk of serious infections was lower for certolizumab pegol (adjusted hazard ratio, 0.75; 95% CI, 0.58-0.97). Etanercept was used as the reference arm for comparison since it was the most widely prescribed drug in the registry.

That finding is in “direct contradiction” to a 2011 Cochrane review finding that certolizumab pegol was associated with an infection rate three to four times higher than other anti–tumor necrosis factor (anti-TNF) drugs (Cochrane Database Syst Rev. 2011;2:Cd008794), the authors noted.

SOURCE: Rutherford AI et al. Ann Rheum Dis. 2018 Mar 28. doi: 10.1136/annrheumdis-2017-212825.

Wound protection devices could significantly decrease the risk of surgical site infections after lower gastrointestinal surgery, particularly dual-ring devices, new research suggests.

A meta-analysis of 12 randomized, controlled trials with 3,029 participants found that the use of wound protectors during surgery was associated with 34% lower odds of surgical site infection (95% confidence interval, 0.45–0.90; P less than .01).

SOURCE: Zhang L et al. Surg Endosc. 2018;32:1111–22.

Wound protection devices could significantly decrease the risk of surgical site infections after lower gastrointestinal surgery, particularly dual-ring devices, new research suggests.

A meta-analysis of 12 randomized, controlled trials with 3,029 participants found that the use of wound protectors during surgery was associated with 34% lower odds of surgical site infection (95% confidence interval, 0.45–0.90; P less than .01).

SOURCE: Zhang L et al. Surg Endosc. 2018;32:1111–22.

Wound protection devices could significantly decrease the risk of surgical site infections after lower gastrointestinal surgery, particularly dual-ring devices, new research suggests.

A meta-analysis of 12 randomized, controlled trials with 3,029 participants found that the use of wound protectors during surgery was associated with 34% lower odds of surgical site infection (95% confidence interval, 0.45–0.90; P less than .01).

SOURCE: Zhang L et al. Surg Endosc. 2018;32:1111–22.

SAN DIEGO—A novel therapy designed to promote the maturation and activation of myelin-producing oligodendrocytes is moving to phase II clinical trials based on evidence of safety and efficacy in animal models and humans. The therapy, a suspension of clean-surfaced gold nanocrystals, may remyelinate multiple sclerosis (MS) lesions, according to research presented at the ACTRIMS 2018 Forum.

This agent, known as CNM-Au8, has been associated with improved behavioral function in animal models of MS, according to Michael Hotchkin, Head of Strategic Oper­ations at Clene Nanomedicine in Salt Lake City. Clene Nanomedicine is developing CNM-Au8. Although the mechanism of action is “multifactorial,” the benefit has been linked to bioenergetic support for the differentiation and maturation of oligodendrocyte precursor cells, said Mr. Hotchkin.

In one behavioral study of fine motor kinetics in an experimental model of MS, mice treated with CNM-Au8 “were effectively indistinguishable” from animals with no demyelination, he said.

Treatment Improved Two Models of Demyelination

Following in vitro studies that suggested that CNM-Au8 can promote the differentiation of oligodendrocyte precursor cells into mature myelin-producing oligodendrocytes, a series of studies was conducted in lysolecithin and cuprizone animal models of MS demyelination.

The studies using the lysolecithin model included vehicle controls and compared CNM-Au8’s effect on remyelinated axons after inducing spinal demyelination with lysolecithin. In the cuprizone studies, the treatments were delivered before injury to test prophylactic efficacy and after injury to test treatment efficacy. Markers of remyelination, such as oligodendrocyte maturation, myelin basic protein expression, and axonal staining, were evaluated by immunohistochemistry and transmission electron microscopy in animals sacrificed at various times after injury.

CNM-Au8 produced “striking visible evidence of progressive increase in myelin,” according to Mr. Hotchkin. The treatment was associated with reductions in myelin sheath degeneration and demyelinated areas, relative to vehicle. In one analysis of the lysolecithin model, CNM-Au8 was associated with a 43% increase in myelinated axon count. Moreover, an increase in mature oligodendrocytes localized at the site of focal demyelination injury in the CNM-Au8-treated animals was consistent with stimulation of oligodendrocyte maturation, according to Mr. Hotchkin.

In both models, investigators found evidence of increased oligodendrocyte maturation and remyelination when CNM-Au8 was administered after injury, as well as when it was administered before injury. The results suggest that CNM-Au8 has important activity in the remyelination of demyelinated axons.

Researchers also conducted behavioral studies in the cuprizone model of MS. They tracked the animals’ movement with lasers and used computer software to analyze the movement. These studies included relevant controls and compared animals with no demyelination, vehicle-treated animals dosed with cuprizone, and CNM-Au8-treated animals similarly dosed with cuprizone, to determine whether delayed treatment following initial damage from the toxin would result in functional recovery in the animals.

The investigators observed protective effects of CNM-Au8 when the drug was administered in this treatment paradigm. Improvements in several behavioral end points when the drug was administered after the demyelinating insult “demonstrated that CNM-Au8 restored behavioral function following demyelination,” said Mr. Hotchkin.

Furthermore, in a behavioral study of fine motor kinetics, function improved by 78% at week 6, compared with week 3 (ie, immediately following the start of treatment) in the group treated with CMN-Au8 that was receiving cuprizone. The animals treated with vehicle and cuprizone had a 39% functional improvement at week 6, compared with week 3. Notably, there was not a statistically significant difference in function at week 6 between CNM-Au8-treated animals and the normal healthy control animals without demyelination, indicating that the functional recovery made the former and latter animals indistinguishable.

Therapy Promotes Bioenergetics Catalysis

CNM-Au8 may generate remyelination by more than one mechanism, said Mr. Hotchkin, and evidence indicates that the drug promotes bioenergetic catalysis that is important to the maturation of oligodendrocyte precursors. Published literature suggests an association between altered oligodendrocyte energy utilization and remyelination failure in the human brain. Other evidence suggests that CNM-Au8 may trigger oligodendrocytes’ remyelinating activity by improving energy sources such as adenosine triphosphate, lactate, and oxidized nicotinamide adenine dinucleotide (NAD+), said Mr. Hotchkin. For example, CNM-Au8 increased NAD+ levels in mouse hippocampal cultures by about 40%, relative to vehicle.

In response to questions about the catalytic mechanism, Mr. Hotchkin responded, “You can fill a car’s tank with gas, but if the electrical system is fouled, the car goes nowhere. CNM-Au8 is the catalytic engine driving bioenergetic improvements in the oligodendrocytes driving them to remyelinate.” Data suggest that CNM-Au8 may have applications in other neurodegenerative diseases, based on the bioenergetic failure hypothesis of neurodegeneration and aging, said Mr. Hotchkin.

Oligodendrocyte precursor cells are known to be present in the human brain in and around MS lesions even years after an MS attack. Thus, the animal studies may be relevant to clinical MS. As an oral agent, CNM-Au8 has the potential to be a major clinical advance if human trials show activity comparable to that in animal studies, said Mr. Hotchkin.

Initial phase I human clinical work and extensive animal toxicology has supported the safety of this agent. Trials in patients with MS that examine clinical end points are planned. “A phase II study in chronic optic neuropathy in relapsing-remitting MS patients will commence in 2018,” Glen Frick, MD, PhD, Chief Medical Officer of Clene Nanomedicine, told Neurology Reviews.

—Ted Bosworth

Suggested Reading

Rone MB, Cui QL, Fang J, et al. Oligodendrogliopathy in multiple sclerosis: low glycolytic metabolic rate promotes oligodendrocyte survival. J Neurosci. 2016;36(17):4698-4707.

SAN DIEGO—A novel therapy designed to promote the maturation and activation of myelin-producing oligodendrocytes is moving to phase II clinical trials based on evidence of safety and efficacy in animal models and humans. The therapy, a suspension of clean-surfaced gold nanocrystals, may remyelinate multiple sclerosis (MS) lesions, according to research presented at the ACTRIMS 2018 Forum.

This agent, known as CNM-Au8, has been associated with improved behavioral function in animal models of MS, according to Michael Hotchkin, Head of Strategic Oper­ations at Clene Nanomedicine in Salt Lake City. Clene Nanomedicine is developing CNM-Au8. Although the mechanism of action is “multifactorial,” the benefit has been linked to bioenergetic support for the differentiation and maturation of oligodendrocyte precursor cells, said Mr. Hotchkin.

In one behavioral study of fine motor kinetics in an experimental model of MS, mice treated with CNM-Au8 “were effectively indistinguishable” from animals with no demyelination, he said.

Treatment Improved Two Models of Demyelination

Following in vitro studies that suggested that CNM-Au8 can promote the differentiation of oligodendrocyte precursor cells into mature myelin-producing oligodendrocytes, a series of studies was conducted in lysolecithin and cuprizone animal models of MS demyelination.

The studies using the lysolecithin model included vehicle controls and compared CNM-Au8’s effect on remyelinated axons after inducing spinal demyelination with lysolecithin. In the cuprizone studies, the treatments were delivered before injury to test prophylactic efficacy and after injury to test treatment efficacy. Markers of remyelination, such as oligodendrocyte maturation, myelin basic protein expression, and axonal staining, were evaluated by immunohistochemistry and transmission electron microscopy in animals sacrificed at various times after injury.

CNM-Au8 produced “striking visible evidence of progressive increase in myelin,” according to Mr. Hotchkin. The treatment was associated with reductions in myelin sheath degeneration and demyelinated areas, relative to vehicle. In one analysis of the lysolecithin model, CNM-Au8 was associated with a 43% increase in myelinated axon count. Moreover, an increase in mature oligodendrocytes localized at the site of focal demyelination injury in the CNM-Au8-treated animals was consistent with stimulation of oligodendrocyte maturation, according to Mr. Hotchkin.

In both models, investigators found evidence of increased oligodendrocyte maturation and remyelination when CNM-Au8 was administered after injury, as well as when it was administered before injury. The results suggest that CNM-Au8 has important activity in the remyelination of demyelinated axons.

Researchers also conducted behavioral studies in the cuprizone model of MS. They tracked the animals’ movement with lasers and used computer software to analyze the movement. These studies included relevant controls and compared animals with no demyelination, vehicle-treated animals dosed with cuprizone, and CNM-Au8-treated animals similarly dosed with cuprizone, to determine whether delayed treatment following initial damage from the toxin would result in functional recovery in the animals.

The investigators observed protective effects of CNM-Au8 when the drug was administered in this treatment paradigm. Improvements in several behavioral end points when the drug was administered after the demyelinating insult “demonstrated that CNM-Au8 restored behavioral function following demyelination,” said Mr. Hotchkin.

Furthermore, in a behavioral study of fine motor kinetics, function improved by 78% at week 6, compared with week 3 (ie, immediately following the start of treatment) in the group treated with CMN-Au8 that was receiving cuprizone. The animals treated with vehicle and cuprizone had a 39% functional improvement at week 6, compared with week 3. Notably, there was not a statistically significant difference in function at week 6 between CNM-Au8-treated animals and the normal healthy control animals without demyelination, indicating that the functional recovery made the former and latter animals indistinguishable.

Therapy Promotes Bioenergetics Catalysis

CNM-Au8 may generate remyelination by more than one mechanism, said Mr. Hotchkin, and evidence indicates that the drug promotes bioenergetic catalysis that is important to the maturation of oligodendrocyte precursors. Published literature suggests an association between altered oligodendrocyte energy utilization and remyelination failure in the human brain. Other evidence suggests that CNM-Au8 may trigger oligodendrocytes’ remyelinating activity by improving energy sources such as adenosine triphosphate, lactate, and oxidized nicotinamide adenine dinucleotide (NAD+), said Mr. Hotchkin. For example, CNM-Au8 increased NAD+ levels in mouse hippocampal cultures by about 40%, relative to vehicle.

In response to questions about the catalytic mechanism, Mr. Hotchkin responded, “You can fill a car’s tank with gas, but if the electrical system is fouled, the car goes nowhere. CNM-Au8 is the catalytic engine driving bioenergetic improvements in the oligodendrocytes driving them to remyelinate.” Data suggest that CNM-Au8 may have applications in other neurodegenerative diseases, based on the bioenergetic failure hypothesis of neurodegeneration and aging, said Mr. Hotchkin.

Oligodendrocyte precursor cells are known to be present in the human brain in and around MS lesions even years after an MS attack. Thus, the animal studies may be relevant to clinical MS. As an oral agent, CNM-Au8 has the potential to be a major clinical advance if human trials show activity comparable to that in animal studies, said Mr. Hotchkin.

Initial phase I human clinical work and extensive animal toxicology has supported the safety of this agent. Trials in patients with MS that examine clinical end points are planned. “A phase II study in chronic optic neuropathy in relapsing-remitting MS patients will commence in 2018,” Glen Frick, MD, PhD, Chief Medical Officer of Clene Nanomedicine, told Neurology Reviews.

—Ted Bosworth

Suggested Reading

Rone MB, Cui QL, Fang J, et al. Oligodendrogliopathy in multiple sclerosis: low glycolytic metabolic rate promotes oligodendrocyte survival. J Neurosci. 2016;36(17):4698-4707.

SAN DIEGO—A novel therapy designed to promote the maturation and activation of myelin-producing oligodendrocytes is moving to phase II clinical trials based on evidence of safety and efficacy in animal models and humans. The therapy, a suspension of clean-surfaced gold nanocrystals, may remyelinate multiple sclerosis (MS) lesions, according to research presented at the ACTRIMS 2018 Forum.

This agent, known as CNM-Au8, has been associated with improved behavioral function in animal models of MS, according to Michael Hotchkin, Head of Strategic Oper­ations at Clene Nanomedicine in Salt Lake City. Clene Nanomedicine is developing CNM-Au8. Although the mechanism of action is “multifactorial,” the benefit has been linked to bioenergetic support for the differentiation and maturation of oligodendrocyte precursor cells, said Mr. Hotchkin.

In one behavioral study of fine motor kinetics in an experimental model of MS, mice treated with CNM-Au8 “were effectively indistinguishable” from animals with no demyelination, he said.

Treatment Improved Two Models of Demyelination

Following in vitro studies that suggested that CNM-Au8 can promote the differentiation of oligodendrocyte precursor cells into mature myelin-producing oligodendrocytes, a series of studies was conducted in lysolecithin and cuprizone animal models of MS demyelination.

The studies using the lysolecithin model included vehicle controls and compared CNM-Au8’s effect on remyelinated axons after inducing spinal demyelination with lysolecithin. In the cuprizone studies, the treatments were delivered before injury to test prophylactic efficacy and after injury to test treatment efficacy. Markers of remyelination, such as oligodendrocyte maturation, myelin basic protein expression, and axonal staining, were evaluated by immunohistochemistry and transmission electron microscopy in animals sacrificed at various times after injury.

CNM-Au8 produced “striking visible evidence of progressive increase in myelin,” according to Mr. Hotchkin. The treatment was associated with reductions in myelin sheath degeneration and demyelinated areas, relative to vehicle. In one analysis of the lysolecithin model, CNM-Au8 was associated with a 43% increase in myelinated axon count. Moreover, an increase in mature oligodendrocytes localized at the site of focal demyelination injury in the CNM-Au8-treated animals was consistent with stimulation of oligodendrocyte maturation, according to Mr. Hotchkin.

In both models, investigators found evidence of increased oligodendrocyte maturation and remyelination when CNM-Au8 was administered after injury, as well as when it was administered before injury. The results suggest that CNM-Au8 has important activity in the remyelination of demyelinated axons.

Researchers also conducted behavioral studies in the cuprizone model of MS. They tracked the animals’ movement with lasers and used computer software to analyze the movement. These studies included relevant controls and compared animals with no demyelination, vehicle-treated animals dosed with cuprizone, and CNM-Au8-treated animals similarly dosed with cuprizone, to determine whether delayed treatment following initial damage from the toxin would result in functional recovery in the animals.

The investigators observed protective effects of CNM-Au8 when the drug was administered in this treatment paradigm. Improvements in several behavioral end points when the drug was administered after the demyelinating insult “demonstrated that CNM-Au8 restored behavioral function following demyelination,” said Mr. Hotchkin.

Furthermore, in a behavioral study of fine motor kinetics, function improved by 78% at week 6, compared with week 3 (ie, immediately following the start of treatment) in the group treated with CMN-Au8 that was receiving cuprizone. The animals treated with vehicle and cuprizone had a 39% functional improvement at week 6, compared with week 3. Notably, there was not a statistically significant difference in function at week 6 between CNM-Au8-treated animals and the normal healthy control animals without demyelination, indicating that the functional recovery made the former and latter animals indistinguishable.

Therapy Promotes Bioenergetics Catalysis

CNM-Au8 may generate remyelination by more than one mechanism, said Mr. Hotchkin, and evidence indicates that the drug promotes bioenergetic catalysis that is important to the maturation of oligodendrocyte precursors. Published literature suggests an association between altered oligodendrocyte energy utilization and remyelination failure in the human brain. Other evidence suggests that CNM-Au8 may trigger oligodendrocytes’ remyelinating activity by improving energy sources such as adenosine triphosphate, lactate, and oxidized nicotinamide adenine dinucleotide (NAD+), said Mr. Hotchkin. For example, CNM-Au8 increased NAD+ levels in mouse hippocampal cultures by about 40%, relative to vehicle.

In response to questions about the catalytic mechanism, Mr. Hotchkin responded, “You can fill a car’s tank with gas, but if the electrical system is fouled, the car goes nowhere. CNM-Au8 is the catalytic engine driving bioenergetic improvements in the oligodendrocytes driving them to remyelinate.” Data suggest that CNM-Au8 may have applications in other neurodegenerative diseases, based on the bioenergetic failure hypothesis of neurodegeneration and aging, said Mr. Hotchkin.

Oligodendrocyte precursor cells are known to be present in the human brain in and around MS lesions even years after an MS attack. Thus, the animal studies may be relevant to clinical MS. As an oral agent, CNM-Au8 has the potential to be a major clinical advance if human trials show activity comparable to that in animal studies, said Mr. Hotchkin.

Initial phase I human clinical work and extensive animal toxicology has supported the safety of this agent. Trials in patients with MS that examine clinical end points are planned. “A phase II study in chronic optic neuropathy in relapsing-remitting MS patients will commence in 2018,” Glen Frick, MD, PhD, Chief Medical Officer of Clene Nanomedicine, told Neurology Reviews.

—Ted Bosworth

Suggested Reading

Rone MB, Cui QL, Fang J, et al. Oligodendrogliopathy in multiple sclerosis: low glycolytic metabolic rate promotes oligodendrocyte survival. J Neurosci. 2016;36(17):4698-4707.

Children prescribed histamine₂-receptor antagonists (H₂RAs), proton pump inhibitors (PPIs), or antibiotics during the first 6 months of life may be at greater risk of developing allergic disease, research suggests.

A retrospective cohort study looked at the incidence of subsequent allergic disease in 792,130 children, 7.6% of whom were prescribed an H₂RA, 1.7% were prescribed a PPI, and 16.6% were prescribed an antibiotic during the first 6 months of life.

Children who were prescribed a H₂RA or a PPI had a greater than twofold higher incidence of food allergy (adjusted hazard ratios 2.18 and 2.59, respectively), reported Edward Mitre, MD, of the Uniformed Services University of the Health Sciences, Bethesda, Md., and his coauthors, reported in the April 2 online edition of JAMA Pediatrics.

In particular, the use of acid-suppressing medications was associated with a 2.4-fold increase in the risk of being diagnosed with cow’s milk allergy, while the risk of egg allergy was 74% higher in children prescribed an H₂RA and 35% higher in children prescribed a PPI. In children prescribed an H₂RA, the risk of peanut allergy was 21% higher, and in children prescribed a PPI, it was 27% higher.

There also was a dose-dependent interaction between the duration of medication and risk of food allergy. Children who were prescribed more than 60 days of PPIs had a 52% higher risk than did those who were prescribed 1-60 days, and a similar but slightly lower increased risk was seen in those prescribed more than 60 days of H₂RAs (hazard ratio, 1.32).

Acid-suppressing medication use also was associated with an increased risk of nonfood allergies, in particular medication allergy (adjusted HR, 1.70 for H₂RAs and 1.84 for PPIs), allergic rhinitis (aHR, 1.50 for H₂RAs and 1.44 for PPIs), anaphylaxis (aHR, 1.51 for H₂RAs and 1.45 for PPIs).

Infants prescribed acid-suppressing medication also showed higher rates of asthma, allergic conjunctivitis, and urticaria during childhood.

SOURCE: Mitre E et al. JAMA Pediatrics. 2018 Apr 2. doi: 10.1001/jamapediatrics.2018.0315.

Children prescribed histamine₂-receptor antagonists (H₂RAs), proton pump inhibitors (PPIs), or antibiotics during the first 6 months of life may be at greater risk of developing allergic disease, research suggests.

A retrospective cohort study looked at the incidence of subsequent allergic disease in 792,130 children, 7.6% of whom were prescribed an H₂RA, 1.7% were prescribed a PPI, and 16.6% were prescribed an antibiotic during the first 6 months of life.

Children who were prescribed a H₂RA or a PPI had a greater than twofold higher incidence of food allergy (adjusted hazard ratios 2.18 and 2.59, respectively), reported Edward Mitre, MD, of the Uniformed Services University of the Health Sciences, Bethesda, Md., and his coauthors, reported in the April 2 online edition of JAMA Pediatrics.

In particular, the use of acid-suppressing medications was associated with a 2.4-fold increase in the risk of being diagnosed with cow’s milk allergy, while the risk of egg allergy was 74% higher in children prescribed an H₂RA and 35% higher in children prescribed a PPI. In children prescribed an H₂RA, the risk of peanut allergy was 21% higher, and in children prescribed a PPI, it was 27% higher.

There also was a dose-dependent interaction between the duration of medication and risk of food allergy. Children who were prescribed more than 60 days of PPIs had a 52% higher risk than did those who were prescribed 1-60 days, and a similar but slightly lower increased risk was seen in those prescribed more than 60 days of H₂RAs (hazard ratio, 1.32).

Acid-suppressing medication use also was associated with an increased risk of nonfood allergies, in particular medication allergy (adjusted HR, 1.70 for H₂RAs and 1.84 for PPIs), allergic rhinitis (aHR, 1.50 for H₂RAs and 1.44 for PPIs), anaphylaxis (aHR, 1.51 for H₂RAs and 1.45 for PPIs).

Infants prescribed acid-suppressing medication also showed higher rates of asthma, allergic conjunctivitis, and urticaria during childhood.

SOURCE: Mitre E et al. JAMA Pediatrics. 2018 Apr 2. doi: 10.1001/jamapediatrics.2018.0315.

Children prescribed histamine₂-receptor antagonists (H₂RAs), proton pump inhibitors (PPIs), or antibiotics during the first 6 months of life may be at greater risk of developing allergic disease, research suggests.

A retrospective cohort study looked at the incidence of subsequent allergic disease in 792,130 children, 7.6% of whom were prescribed an H₂RA, 1.7% were prescribed a PPI, and 16.6% were prescribed an antibiotic during the first 6 months of life.

Children who were prescribed a H₂RA or a PPI had a greater than twofold higher incidence of food allergy (adjusted hazard ratios 2.18 and 2.59, respectively), reported Edward Mitre, MD, of the Uniformed Services University of the Health Sciences, Bethesda, Md., and his coauthors, reported in the April 2 online edition of JAMA Pediatrics.

In particular, the use of acid-suppressing medications was associated with a 2.4-fold increase in the risk of being diagnosed with cow’s milk allergy, while the risk of egg allergy was 74% higher in children prescribed an H₂RA and 35% higher in children prescribed a PPI. In children prescribed an H₂RA, the risk of peanut allergy was 21% higher, and in children prescribed a PPI, it was 27% higher.

There also was a dose-dependent interaction between the duration of medication and risk of food allergy. Children who were prescribed more than 60 days of PPIs had a 52% higher risk than did those who were prescribed 1-60 days, and a similar but slightly lower increased risk was seen in those prescribed more than 60 days of H₂RAs (hazard ratio, 1.32).

Acid-suppressing medication use also was associated with an increased risk of nonfood allergies, in particular medication allergy (adjusted HR, 1.70 for H₂RAs and 1.84 for PPIs), allergic rhinitis (aHR, 1.50 for H₂RAs and 1.44 for PPIs), anaphylaxis (aHR, 1.51 for H₂RAs and 1.45 for PPIs).

Infants prescribed acid-suppressing medication also showed higher rates of asthma, allergic conjunctivitis, and urticaria during childhood.

SOURCE: Mitre E et al. JAMA Pediatrics. 2018 Apr 2. doi: 10.1001/jamapediatrics.2018.0315.

Despite a wide gap between male and female neurologists, both in terms of academic faculty rank and number of publications, there may be some good news for women in this medical field.

A recent study of the 1,712 academic neurologists across 29 top-ranked neurology programs revealed that 1,184 (69%) were men and 528 (31%) were women, and men outnumbered women in all academic faculty ranks with a gap that increased as the rank advanced. For example, at the rank of instructor/lecturer, the male-to-female ratio was 59% to 41%. The gap only widens from there: assistant professor (57% male), associate professor (70%), and professor (86%).

Thinkstock photo

For example, the authors note that there are a variety of explanations for the gender gap in both rank and publication, including asymmetric home or childcare responsibilities, cultural stereotypes, professional isolation, and different career motivations, though the study was not able to account for those variables.

“Compared with men, women may be more likely to be recruited for employment positions that emphasize teaching and mentoring rather than research, or women may be more inclined to choose such positions,” the authors noted, adding that academic institutions are moving beyond traditional measures of academic productivity (publication rate, publication impact, and grant support) to recognize other factors, such as the quality and quantity of teaching, the development of educational resources, and administrative effectiveness.

If the numbers reflect persistent barriers to women, “it will be important to develop programs to heighten awareness of diversity in academic neurology,” the authors stated. On the flip side, if the numbers reflect a system that is supporting different goals, “academic neurology departments should be encouraged to foster a variety of career paths and expectations for all faculty.”

The authors reported no conflicts of interest. The study was funded by the Jerry Isler Neuromuscular Fund.

[email protected]

SOURCE: McDermott M et al. JAMA Neurol. 2018 Apr 2. doi: 10.1001/jamaneurol.2018.0275.

Despite a wide gap between male and female neurologists, both in terms of academic faculty rank and number of publications, there may be some good news for women in this medical field.

A recent study of the 1,712 academic neurologists across 29 top-ranked neurology programs revealed that 1,184 (69%) were men and 528 (31%) were women, and men outnumbered women in all academic faculty ranks with a gap that increased as the rank advanced. For example, at the rank of instructor/lecturer, the male-to-female ratio was 59% to 41%. The gap only widens from there: assistant professor (57% male), associate professor (70%), and professor (86%).

Thinkstock photo

For example, the authors note that there are a variety of explanations for the gender gap in both rank and publication, including asymmetric home or childcare responsibilities, cultural stereotypes, professional isolation, and different career motivations, though the study was not able to account for those variables.

“Compared with men, women may be more likely to be recruited for employment positions that emphasize teaching and mentoring rather than research, or women may be more inclined to choose such positions,” the authors noted, adding that academic institutions are moving beyond traditional measures of academic productivity (publication rate, publication impact, and grant support) to recognize other factors, such as the quality and quantity of teaching, the development of educational resources, and administrative effectiveness.

If the numbers reflect persistent barriers to women, “it will be important to develop programs to heighten awareness of diversity in academic neurology,” the authors stated. On the flip side, if the numbers reflect a system that is supporting different goals, “academic neurology departments should be encouraged to foster a variety of career paths and expectations for all faculty.”

The authors reported no conflicts of interest. The study was funded by the Jerry Isler Neuromuscular Fund.

[email protected]

SOURCE: McDermott M et al. JAMA Neurol. 2018 Apr 2. doi: 10.1001/jamaneurol.2018.0275.

Despite a wide gap between male and female neurologists, both in terms of academic faculty rank and number of publications, there may be some good news for women in this medical field.

A recent study of the 1,712 academic neurologists across 29 top-ranked neurology programs revealed that 1,184 (69%) were men and 528 (31%) were women, and men outnumbered women in all academic faculty ranks with a gap that increased as the rank advanced. For example, at the rank of instructor/lecturer, the male-to-female ratio was 59% to 41%. The gap only widens from there: assistant professor (57% male), associate professor (70%), and professor (86%).

Thinkstock photo

For example, the authors note that there are a variety of explanations for the gender gap in both rank and publication, including asymmetric home or childcare responsibilities, cultural stereotypes, professional isolation, and different career motivations, though the study was not able to account for those variables.

“Compared with men, women may be more likely to be recruited for employment positions that emphasize teaching and mentoring rather than research, or women may be more inclined to choose such positions,” the authors noted, adding that academic institutions are moving beyond traditional measures of academic productivity (publication rate, publication impact, and grant support) to recognize other factors, such as the quality and quantity of teaching, the development of educational resources, and administrative effectiveness.

If the numbers reflect persistent barriers to women, “it will be important to develop programs to heighten awareness of diversity in academic neurology,” the authors stated. On the flip side, if the numbers reflect a system that is supporting different goals, “academic neurology departments should be encouraged to foster a variety of career paths and expectations for all faculty.”

The authors reported no conflicts of interest. The study was funded by the Jerry Isler Neuromuscular Fund.

[email protected]

SOURCE: McDermott M et al. JAMA Neurol. 2018 Apr 2. doi: 10.1001/jamaneurol.2018.0275.

Laws covering medical or recreational use of marijuana are associated with reduced rates of opioid prescribing among federal health care program enrollees, results of two recently published investigations show.

In one study, researchers investigated whether medical cannabis access affected opioid prescribing in Medicare Part D, the federal program that subsidizes cost of prescription drugs and drug insurance premiums.

©rozmarina/Thinkstock

However, adult-use marijuana laws were associated with “even-lower” opioid prescribing rates, something that had not been investigated previously, according to Dr. Wen, who is with the University of Kentucky, Lexington, and Dr. Hockenberry of Emory University, Atlanta.

“Medical and adult-use marijuana laws have the potential to lower opioid prescribing for Medicaid enrollees, a high-risk population for chronic pain, opioid use disorder, and opioid overdose,” Dr. Wen and Dr. Hockenberry wrote in their report on the study, a cross-sectional analysis including all Medicaid fee-for-service and managed care enrollees during 2011-2016.

The rate of opioid prescribing in the study was –5.88% lower (95% confidence interval, –11.55% to approximately –0.21%) in association with medical marijuana laws, and –6.38% lower (95% CI, –12.20% to approximately –0.56%) for adult-use laws, they reported.

Based on those findings, policy discussions about the opioid epidemic should include the potential for liberalization of marijuana policies to reduce prescription opioid use and consequences in Medicaid enrollees, Dr. Wen and Dr. Hockenberry concluded.

However, legal marijuana alone won’t solve the opioid epidemic, they cautioned.

“As with other policies evaluated in the previous literature, marijuana liberalization is but one potential aspect of a comprehensive package to tackle the epidemic,” they said in the article.

None of the study authors reported conflicts of interest.

SOURCES: Bradford AC et al. JAMA Intern Med. 2018 Apr 2. doi: 10.1001/jamainternmed.2018.0266; Wen H, Hockenberry JM. JAMA Intern Med. 2018 Apr 2. doi: 10.1001/jamainternmed.2018.1007.

Laws covering medical or recreational use of marijuana are associated with reduced rates of opioid prescribing among federal health care program enrollees, results of two recently published investigations show.

In one study, researchers investigated whether medical cannabis access affected opioid prescribing in Medicare Part D, the federal program that subsidizes cost of prescription drugs and drug insurance premiums.

©rozmarina/Thinkstock

However, adult-use marijuana laws were associated with “even-lower” opioid prescribing rates, something that had not been investigated previously, according to Dr. Wen, who is with the University of Kentucky, Lexington, and Dr. Hockenberry of Emory University, Atlanta.

“Medical and adult-use marijuana laws have the potential to lower opioid prescribing for Medicaid enrollees, a high-risk population for chronic pain, opioid use disorder, and opioid overdose,” Dr. Wen and Dr. Hockenberry wrote in their report on the study, a cross-sectional analysis including all Medicaid fee-for-service and managed care enrollees during 2011-2016.

The rate of opioid prescribing in the study was –5.88% lower (95% confidence interval, –11.55% to approximately –0.21%) in association with medical marijuana laws, and –6.38% lower (95% CI, –12.20% to approximately –0.56%) for adult-use laws, they reported.

Based on those findings, policy discussions about the opioid epidemic should include the potential for liberalization of marijuana policies to reduce prescription opioid use and consequences in Medicaid enrollees, Dr. Wen and Dr. Hockenberry concluded.

However, legal marijuana alone won’t solve the opioid epidemic, they cautioned.

“As with other policies evaluated in the previous literature, marijuana liberalization is but one potential aspect of a comprehensive package to tackle the epidemic,” they said in the article.

None of the study authors reported conflicts of interest.

SOURCES: Bradford AC et al. JAMA Intern Med. 2018 Apr 2. doi: 10.1001/jamainternmed.2018.0266; Wen H, Hockenberry JM. JAMA Intern Med. 2018 Apr 2. doi: 10.1001/jamainternmed.2018.1007.

Laws covering medical or recreational use of marijuana are associated with reduced rates of opioid prescribing among federal health care program enrollees, results of two recently published investigations show.

In one study, researchers investigated whether medical cannabis access affected opioid prescribing in Medicare Part D, the federal program that subsidizes cost of prescription drugs and drug insurance premiums.

©rozmarina/Thinkstock

However, adult-use marijuana laws were associated with “even-lower” opioid prescribing rates, something that had not been investigated previously, according to Dr. Wen, who is with the University of Kentucky, Lexington, and Dr. Hockenberry of Emory University, Atlanta.

“Medical and adult-use marijuana laws have the potential to lower opioid prescribing for Medicaid enrollees, a high-risk population for chronic pain, opioid use disorder, and opioid overdose,” Dr. Wen and Dr. Hockenberry wrote in their report on the study, a cross-sectional analysis including all Medicaid fee-for-service and managed care enrollees during 2011-2016.

The rate of opioid prescribing in the study was –5.88% lower (95% confidence interval, –11.55% to approximately –0.21%) in association with medical marijuana laws, and –6.38% lower (95% CI, –12.20% to approximately –0.56%) for adult-use laws, they reported.

Based on those findings, policy discussions about the opioid epidemic should include the potential for liberalization of marijuana policies to reduce prescription opioid use and consequences in Medicaid enrollees, Dr. Wen and Dr. Hockenberry concluded.

However, legal marijuana alone won’t solve the opioid epidemic, they cautioned.

“As with other policies evaluated in the previous literature, marijuana liberalization is but one potential aspect of a comprehensive package to tackle the epidemic,” they said in the article.

None of the study authors reported conflicts of interest.

SOURCES: Bradford AC et al. JAMA Intern Med. 2018 Apr 2. doi: 10.1001/jamainternmed.2018.0266; Wen H, Hockenberry JM. JAMA Intern Med. 2018 Apr 2. doi: 10.1001/jamainternmed.2018.1007.

Pediatric alopecia areata (AA) is more likely to affect girls, but boys are likely to have more severe types of the disorder, reported Iris Wohlmuth-Wieser, MD, of the department of dermatology, MD Anderson Cancer Center, Houston, and her associates, who conducted a large review of U.S. registry data.

Although it is the third most common dermatosis in children, there are not much data on AA in children, so the researchers used information from the National Alopecia Areata Registry, which was established in 2000. First, interested patients and parents were contacted and asked to fill out a web-based screening questionnaire. In the second phase, they were asked to fill out a more extensive survey and visit one of five U.S. sites for a clinical exam by a dermatologist.

Of the 2,218 children and teens who completed the initial questionnaire, the mean age at the time of the survey was 10 years, and their mean age of onset of AA was 6 years. The female to male ratio was 1.5:1; boys were significantly more likely to have severe types of AA (P = .009). Most patients (70%) were white, followed by mixed ethnicity (11%), Hispanic (3%), and then other ethnicities. About 3% of patients said they had a sibling with AA, 14% said that another first-degree relative had AA, and 8% said that at least three first-degree relatives had AA.

In terms of the degree of hair loss, 45% lost all scalp hair, 31% lost all body hair, and 14% lost all nails.

Concomitant diseases were reported by 47% of the responders, with atopic dermatitis, asthma, hay fever, and allergies the most common.

Of the 643 children and teens who completed a more detailed questionnaire and underwent clinical examination, 63% were female; 26% had at least one relative with AA and 8% had at least three first-degree relatives with AA. Almost 4% had congenital AA.

At the physical exam, there were data on the amount of hair loss in 617 children: Of these children, 37% had lost all scalp hair and 19% had lost up to three-quarters of their scalp hair. In 618 children (in whom information on body hair loss was obtained at the physical exam), 72% lost all or some of their body hair. Information on nails was available in 609 children; in this group, 44% had some nail involvement. More detailed information was available in 290 children; in this group, findings included pitting in 86%, dystrophy in 10%, onycholysis in 2%, ridging in 1%, and onychomycosis in 1%.

Commenting on the 25 children who presented with congenital AA, the authors wrote that this is “an extremely rare and infrequently reported form of AA.

“This is an interesting and important finding, because AA has traditionally been described as an acquired disease,” they added.

In their cohort overall, 25% had a family history of AA, with 8% having more than three first-degree relatives with AA. The researchers said that the percentage of children with AA and a positive family history ranges from 8% to 52% in the literature.

“The predominant presentation of AA types in our cohort (61.4%) was severe hair loss (76%-100% of scalp hair loss). This is comparable with a European study reporting a prevalence of 65%. Other studies on childhood AA conducted in Asian and Arab populations observed mainly mild cases,” they wrote.

Nail involvement, often reported with AA, was evident in 39% of patients who completed the questionnaire online and in 44% on physical exam. This agreed with the 26%-40% involvement reported in the literature.

There were no conflicts of interest or funding information reported.

SOURCE: Wohlmuth-Wieser I et al. Pediatr Dermatol. 2018 Jan 15. doi: 10.1111/pde.13387.

Pediatric alopecia areata (AA) is more likely to affect girls, but boys are likely to have more severe types of the disorder, reported Iris Wohlmuth-Wieser, MD, of the department of dermatology, MD Anderson Cancer Center, Houston, and her associates, who conducted a large review of U.S. registry data.

Although it is the third most common dermatosis in children, there are not much data on AA in children, so the researchers used information from the National Alopecia Areata Registry, which was established in 2000. First, interested patients and parents were contacted and asked to fill out a web-based screening questionnaire. In the second phase, they were asked to fill out a more extensive survey and visit one of five U.S. sites for a clinical exam by a dermatologist.

Of the 2,218 children and teens who completed the initial questionnaire, the mean age at the time of the survey was 10 years, and their mean age of onset of AA was 6 years. The female to male ratio was 1.5:1; boys were significantly more likely to have severe types of AA (P = .009). Most patients (70%) were white, followed by mixed ethnicity (11%), Hispanic (3%), and then other ethnicities. About 3% of patients said they had a sibling with AA, 14% said that another first-degree relative had AA, and 8% said that at least three first-degree relatives had AA.

In terms of the degree of hair loss, 45% lost all scalp hair, 31% lost all body hair, and 14% lost all nails.

Concomitant diseases were reported by 47% of the responders, with atopic dermatitis, asthma, hay fever, and allergies the most common.

Of the 643 children and teens who completed a more detailed questionnaire and underwent clinical examination, 63% were female; 26% had at least one relative with AA and 8% had at least three first-degree relatives with AA. Almost 4% had congenital AA.

At the physical exam, there were data on the amount of hair loss in 617 children: Of these children, 37% had lost all scalp hair and 19% had lost up to three-quarters of their scalp hair. In 618 children (in whom information on body hair loss was obtained at the physical exam), 72% lost all or some of their body hair. Information on nails was available in 609 children; in this group, 44% had some nail involvement. More detailed information was available in 290 children; in this group, findings included pitting in 86%, dystrophy in 10%, onycholysis in 2%, ridging in 1%, and onychomycosis in 1%.

Commenting on the 25 children who presented with congenital AA, the authors wrote that this is “an extremely rare and infrequently reported form of AA.

“This is an interesting and important finding, because AA has traditionally been described as an acquired disease,” they added.

In their cohort overall, 25% had a family history of AA, with 8% having more than three first-degree relatives with AA. The researchers said that the percentage of children with AA and a positive family history ranges from 8% to 52% in the literature.

“The predominant presentation of AA types in our cohort (61.4%) was severe hair loss (76%-100% of scalp hair loss). This is comparable with a European study reporting a prevalence of 65%. Other studies on childhood AA conducted in Asian and Arab populations observed mainly mild cases,” they wrote.

Nail involvement, often reported with AA, was evident in 39% of patients who completed the questionnaire online and in 44% on physical exam. This agreed with the 26%-40% involvement reported in the literature.

There were no conflicts of interest or funding information reported.

SOURCE: Wohlmuth-Wieser I et al. Pediatr Dermatol. 2018 Jan 15. doi: 10.1111/pde.13387.

Pediatric alopecia areata (AA) is more likely to affect girls, but boys are likely to have more severe types of the disorder, reported Iris Wohlmuth-Wieser, MD, of the department of dermatology, MD Anderson Cancer Center, Houston, and her associates, who conducted a large review of U.S. registry data.

Although it is the third most common dermatosis in children, there are not much data on AA in children, so the researchers used information from the National Alopecia Areata Registry, which was established in 2000. First, interested patients and parents were contacted and asked to fill out a web-based screening questionnaire. In the second phase, they were asked to fill out a more extensive survey and visit one of five U.S. sites for a clinical exam by a dermatologist.

Of the 2,218 children and teens who completed the initial questionnaire, the mean age at the time of the survey was 10 years, and their mean age of onset of AA was 6 years. The female to male ratio was 1.5:1; boys were significantly more likely to have severe types of AA (P = .009). Most patients (70%) were white, followed by mixed ethnicity (11%), Hispanic (3%), and then other ethnicities. About 3% of patients said they had a sibling with AA, 14% said that another first-degree relative had AA, and 8% said that at least three first-degree relatives had AA.

In terms of the degree of hair loss, 45% lost all scalp hair, 31% lost all body hair, and 14% lost all nails.

Concomitant diseases were reported by 47% of the responders, with atopic dermatitis, asthma, hay fever, and allergies the most common.

Of the 643 children and teens who completed a more detailed questionnaire and underwent clinical examination, 63% were female; 26% had at least one relative with AA and 8% had at least three first-degree relatives with AA. Almost 4% had congenital AA.

At the physical exam, there were data on the amount of hair loss in 617 children: Of these children, 37% had lost all scalp hair and 19% had lost up to three-quarters of their scalp hair. In 618 children (in whom information on body hair loss was obtained at the physical exam), 72% lost all or some of their body hair. Information on nails was available in 609 children; in this group, 44% had some nail involvement. More detailed information was available in 290 children; in this group, findings included pitting in 86%, dystrophy in 10%, onycholysis in 2%, ridging in 1%, and onychomycosis in 1%.

Commenting on the 25 children who presented with congenital AA, the authors wrote that this is “an extremely rare and infrequently reported form of AA.

“This is an interesting and important finding, because AA has traditionally been described as an acquired disease,” they added.

In their cohort overall, 25% had a family history of AA, with 8% having more than three first-degree relatives with AA. The researchers said that the percentage of children with AA and a positive family history ranges from 8% to 52% in the literature.

“The predominant presentation of AA types in our cohort (61.4%) was severe hair loss (76%-100% of scalp hair loss). This is comparable with a European study reporting a prevalence of 65%. Other studies on childhood AA conducted in Asian and Arab populations observed mainly mild cases,” they wrote.

Nail involvement, often reported with AA, was evident in 39% of patients who completed the questionnaire online and in 44% on physical exam. This agreed with the 26%-40% involvement reported in the literature.

There were no conflicts of interest or funding information reported.

SOURCE: Wohlmuth-Wieser I et al. Pediatr Dermatol. 2018 Jan 15. doi: 10.1111/pde.13387.

Topical oxybutynin 3% gel reduced the severity of axillary hyperhidrosis in teens and young adults and improved their quality of life, in a prospective pilot study, Nicholas V. Nguyen, MD, of the division of dermatology, Akron Children’s Hospital, Ohio, and his associates reported.

Ten patients aged 13-24 years with moderate to severe axillary hyperhidrosis started the study and were treated with 1 g of oxybutynin 3% gel applied to each axilla every morning for 4 weeks. Of the seven patients who completed the study, four had a two-point reduction in the Hyperhidrosis Disease Severity Scale (HDSS) at week 1 and all seven achieved that endpoint at week 4. Of the five patients who also had hyperhidrosis of the palms, four had a two-point reduction in the HDSS at weeks 1 and 4; the remaining patient reported no change. Of the five patients who also had plantar hyperhidrosis, two reported a reduction at weeks 1 and 4, two reported no change, and one had no change at week 1 and experienced worse hyperhidrosis at week 4.

Miyuki-3

One patient developed pyelonephritis on the sixth day of treatment, possibly related to the study drug. “This patient had a history of kidney transplantation, immunosuppression, and recurrent urinary tract infections. For these reasons, the drug should be used with caution in patients with a history of urinary retention or recurrent urinary tract infections,” Dr. Nguyen and his colleagues said.

The manufacturer discontinued the 3% formulation during enrollment, because of business reasons. A large, randomized, placebo-controlled, double-blind trial to address unanswered questions is warranted, the researchers noted. Oxybutynin 10% gel, approved for treating overactive bladder, is still commercially available.

The study was supported by a Society for Pediatric Dermatology pilot project grant and a Colorado Clinical and Translational Sciences Institute grant.

SOURCE: Nguyen NV et al. Pediatr Dermatol. 2018 Jan 15. doi: 10.1111/pde.13404.

Topical oxybutynin 3% gel reduced the severity of axillary hyperhidrosis in teens and young adults and improved their quality of life, in a prospective pilot study, Nicholas V. Nguyen, MD, of the division of dermatology, Akron Children’s Hospital, Ohio, and his associates reported.

Ten patients aged 13-24 years with moderate to severe axillary hyperhidrosis started the study and were treated with 1 g of oxybutynin 3% gel applied to each axilla every morning for 4 weeks. Of the seven patients who completed the study, four had a two-point reduction in the Hyperhidrosis Disease Severity Scale (HDSS) at week 1 and all seven achieved that endpoint at week 4. Of the five patients who also had hyperhidrosis of the palms, four had a two-point reduction in the HDSS at weeks 1 and 4; the remaining patient reported no change. Of the five patients who also had plantar hyperhidrosis, two reported a reduction at weeks 1 and 4, two reported no change, and one had no change at week 1 and experienced worse hyperhidrosis at week 4.

Miyuki-3

One patient developed pyelonephritis on the sixth day of treatment, possibly related to the study drug. “This patient had a history of kidney transplantation, immunosuppression, and recurrent urinary tract infections. For these reasons, the drug should be used with caution in patients with a history of urinary retention or recurrent urinary tract infections,” Dr. Nguyen and his colleagues said.

The manufacturer discontinued the 3% formulation during enrollment, because of business reasons. A large, randomized, placebo-controlled, double-blind trial to address unanswered questions is warranted, the researchers noted. Oxybutynin 10% gel, approved for treating overactive bladder, is still commercially available.

The study was supported by a Society for Pediatric Dermatology pilot project grant and a Colorado Clinical and Translational Sciences Institute grant.

SOURCE: Nguyen NV et al. Pediatr Dermatol. 2018 Jan 15. doi: 10.1111/pde.13404.

Topical oxybutynin 3% gel reduced the severity of axillary hyperhidrosis in teens and young adults and improved their quality of life, in a prospective pilot study, Nicholas V. Nguyen, MD, of the division of dermatology, Akron Children’s Hospital, Ohio, and his associates reported.

Ten patients aged 13-24 years with moderate to severe axillary hyperhidrosis started the study and were treated with 1 g of oxybutynin 3% gel applied to each axilla every morning for 4 weeks. Of the seven patients who completed the study, four had a two-point reduction in the Hyperhidrosis Disease Severity Scale (HDSS) at week 1 and all seven achieved that endpoint at week 4. Of the five patients who also had hyperhidrosis of the palms, four had a two-point reduction in the HDSS at weeks 1 and 4; the remaining patient reported no change. Of the five patients who also had plantar hyperhidrosis, two reported a reduction at weeks 1 and 4, two reported no change, and one had no change at week 1 and experienced worse hyperhidrosis at week 4.

Miyuki-3

One patient developed pyelonephritis on the sixth day of treatment, possibly related to the study drug. “This patient had a history of kidney transplantation, immunosuppression, and recurrent urinary tract infections. For these reasons, the drug should be used with caution in patients with a history of urinary retention or recurrent urinary tract infections,” Dr. Nguyen and his colleagues said.

The manufacturer discontinued the 3% formulation during enrollment, because of business reasons. A large, randomized, placebo-controlled, double-blind trial to address unanswered questions is warranted, the researchers noted. Oxybutynin 10% gel, approved for treating overactive bladder, is still commercially available.

The study was supported by a Society for Pediatric Dermatology pilot project grant and a Colorado Clinical and Translational Sciences Institute grant.

SOURCE: Nguyen NV et al. Pediatr Dermatol. 2018 Jan 15. doi: 10.1111/pde.13404.

DR HENRY I am Dr David Henry, the Editor-in-Chief of The Journal of Community and Supportive Oncology (JCSO; JCSO-online.com). I’m with Dr Dan Haller, former Editor-in-Chief of the Journal of Clinical Oncology and currently the Editor-in-Chief of American Society of Clinical Oncology (ASCO) University. He is also my friend and former mentor at University of Pennsylvania Abramson Cancer Center, where he is Professor Emeritus. We’re going to talk about colorectal cancer and a lot of things that came out of the ASCO meeting this year that were practice changing, or certainly interesting and worth further discussion. I thought we’d start talking about the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration, in which for patients with colorectal cancer who were considering adjuvant postoperative therapy, there was a discussion of 3 cycles versus 6 cycles of FOLFOX (fluorouracil [5-FU] plus oxaliplatin) or XELOX (capecitabine plus oxaliplatin, also CAPOX) (Figure 1).¹ Could you comment on what they did, and how that study turned out?

Three of them were individually reported at ASCO this year, and then the totality was presented at the plenary session – the first time in 12 years that a gastrointestinal (GI) cancer trial made the plenary session. The whole point, obviously, is neuropathy. With 6 months of FOLFOX or XELOX, about 13% or more patients will develop grade 3 neuropathy, even if people stop short of the full-cycle length, and that is a big deal for the 50,000 patients or so who get adjuvant therapy. At the plenary session, the data were presented and the next day three individual trials were presented and discussed by Jeff Meyerhardt (of Dana-Farber Cancer Institute, Boston).

There were 6 different trials: a few included rectum, some included stage II, some used CAPOX and FOLFOX-4 or 6. The only trial that used only FOLFOX was the Cancer and Leukemia Group B (CALGB) trial in the United States (US). There was a lot of heterogeneity, but when Dan was around, I asked him whether that was a problem, and he said on the contrary, was a better thing because it allowed for real-life practice.

The primary endpoint of the study was to look for noninferiority of 3 months versus 6 months of treatment. The noninferiority margin was at a hazard ratio of 1.12, so they were willing to barter down a few percentage points from benefit. If you looked at the primary disease-free survival analysis, the hazard ratio was 1.07, which was an absolute difference of 0.9%, favoring 3 months of therapy. But because the hazard ratio crossed the 1.12 boundary, it was considered inconclusive and not proven.

If you looked at the regimens, CAPOX outperformed FOLFOX. That’s a regimen we don’t do much in the US. We tend to use more FOLFOX, but CAPOX looked better. What they then did was look at the different subsets of patients, and the subsets that it was obviously as good in was the group that had T1-3N1 disease, where 3 months of therapy was clearly just as good as 6 months of therapy, with only a 3% risk of grade 3 neuropathy.
 

DR HENRY That would be one to three nodes?

DR HALLER Exactly. That’s about 50% of patients. In the T4N2 patients, neither regimen did very well and the 3-year disease-free survival was in the range of 50%, which is clearly unacceptable. Jeff discussed two things. Why could CAPOX be better? If you do the math, when you do CAPOX, you get more oxaliplatin during the first few months of therapy, because it’s 130 mg every 3 weeks, rather than 85 mg every 2 weeks. His conclusion was, “for my next patient who has T4N2 disease, I’ll offer 6 months of FOLFOX.” The study that really needs to be done in these patients is FOLFOX versus FOLFIRINOX (folinic acid, 5-FU, irinotecan, oxaliplatin) or FOLFOXIRI (folinic acid, 5-FU, oxaliplatin, irinotecan), because we’re clearly not doing well with this population of patients. But for the T1-3N1 disease, discuss the toxicities and logistics of CAPOX or FOLFOX with the patient. They’ll probably offer 3 months of CAPOX.

He discussed the two new trials. One is a study called ARGO, which is being done by the National Surgical Adjuvant Breast and Bowel Project, where people get standard adjuvant chemotherapy, and they’re then randomized to either 24 months of regorafenib 120 mg per day or a placebo. This is an attempt to recreate the transient benefit from bevacizumab in the NSABP C-08 trial. It’s accruing slowly because regorafenib has some toxicity associated with it, but it probably will be completed. Will it continue the benefit as seen in the 12 months of bevacizumab and C-08? We’ll see.

The other, more interesting study is being done in the cooperative groups looking at FOLFOX plus atezolizumab, one of the checkpoint inhibitors. The difficulty here is that only 15% of people with stage III disease have microsatellite instability (MSI)-high tumors, but it’s certainly compelling. This is a straight up comparison. It’s 6 months of FOLFOX in the control arm, or 6 months of FOLFOX plus atezolizumab concurrently for 6 months, and then an additional 6 months of atezolizumab. These are both very fascinating ideas.
 

DR HENRY To go back to one of your original points, this 3 versus 6 months: the neuropathy is significantly less in those getting the 3 months?
 

DR HALLER It went to 3%.
 

DR HENRY We all see that is very bothersome to patients. Before we leave colorectal, I must ask about the right-sided versus left-sided colorectal cancer that we hear a lot about now. Could you comment on how right-sided is worse than left-sided, and do we understand why?

DR HALLER There are two things to consider. If you look back even to simple trials of 5-FU or biochemical modulated 5-FU from 20 years ago, there were clear differences showing worse prognosis in patients with right-sided tumors, so that’s one point to be made. It’s been consistently seen but never acted upon. Then, the explanation for it, possibly, is that the right colon and left colon are two biologically different organs – and they are. Embryologically, the right colon comes from the midgut and the left colon comes from the hindgut, and there were several presentations at ASCO and at prior meetings showing that when you look at different mutations, they differ between the right and left colons. The right-sided tumors are more MSI-high and more BRAF-mutated, left-sided mutations less so.

Then, people started analyzing many of the very large colon cancer trials, including the US trial CALB/SWOG C80405 and the FIRE-3 trials in Europe, where backbone chemotherapy of FOLFIRI or FOLFOX was given with either cetuximab or bevacizumab in RAS wild-type patients. For one study, C80405, they saw that for cetuximab, on the right side, the median survival was 16.7 months and on the left side, it’s 36 months – a 20-month difference. In fact, if you look at the totality of the data, 16.7 almost looks like cetuximab is harming them, as if you were giving it to a RAS-mutated patient, but they were not. They were all RAS wild-type.

For bevacizumab, the right side was 24 months; the left side was 31.4 months. If you look at the left, cetuximab was 36 months and bevacizumab was 31.4 months, so it appears left-sided tumors should get more cetuximab than they are now getting in the US with a 5-month difference, but that decrement is much different on the right, where there’s an 8-month benefit for bevacizumab compared with cetuximab. There is a very good review by Dirk Arnold, who looked at a totality of 6 studies to really examine this more carefully.²

The National Comprehensive Cancer Network has chimed in on this, and is suggesting that for the 25% of people who have right-sided tumors, epidermal growth factor receptor (EGFR) agents not be considered in first-line therapy. NCCN did not go as far to say that EGFR agents should be given on the left side. As I said, the differences are much more impressive in the right, so this is a real sea change for people to consider which side of the tumor affects outcome.

Deb Schrag (Dana-Farber Cancer Institute) presented data at last year’s ASCO not only for stage IV disease showing the same thing, but also stage III disease where there are also right-versus-left differences in terms of recurrence, with a hazard ratio on the right side of about 1.4 compared with the left-sided tumors. Maybe it should be true that 3 months is especially good if you’re treating left-sided tumors, and maybe the right-sided tumor needs to be also calculated with the factors we just talked about. These are two big changes in an area in which we literally haven’t made any change since FOLFOX was introduced a decade ago.

DR HENRY That’s really fascinating, and if not practice changing, then practice challenging. Staying with the mutations idea, in my patients, I’m checking the RAS family and the BRAF mutation, where I’ve learned that’s a particularly bad mutation. I wonder if you might comment on the Kopetz trial, which took a cohort of BRAF mutants and treated them (Figure 2).3 How did that turn out?

DR HALLER It turned out well. We’re turning colon cancer into non–small cell lung cancer in that we’re getting small groups of patients who now have very dedicated care. The backstory here is that there was some thought that you should be treating mutations, not tumor sites. Drugs such as vemurafenib, for example, which is a BRAF inhibitor, worked well in melanoma for the same mutation that’s in colon cancer, V600E. But when vemurafenib was used in the BRAF-mutant patients – these are 10% of the population – median survivorship was one-third that of the rest of the patients, so roughly 12 months. People looked like they were doing worse when vemurafenib was used. They had no benefit.

Scott Kopetz at MD Anderson (Houston, Texas) is a very good bench-to-bed-and-back sort of doc. He looked at this in cell lines and found that when you give a BRAF inhibitor, you upregulate EGFR so you add an EGFR inhibitor. He did a phase 1 and 1B study, and then in the co-operative groups, a study was done – a randomized phase 2 trial for people who had the BRAF-V600E mutation failing first-line therapy, and then went on to receive either irinotecan single agent or irinotecan plus cetuximab or a triple arm of irinotecan, cetuximab, and vemurafenib. There was a crossover, and so the primary endpoint was progression-free survival. It accrued rapidly.

Again, small study, about 100 patients, but for the double-agent arm, or cetuximab–irinotecan, the median survivorship was 2 months. It was 4.4 months for the combination, so more than double. The response rate quadrupled from 4% to 16%, and the people who had disease control tripled, from 22% to 67%. Many of these patients had bulky disease, BRAF mutations. They need response, so this is a very important endpoint.

Overall survival was not different, in part because it was a crossover, and the crossover patients did pretty well. This is going to move more toward first-line therapy, because we don’t talk about fourth- and fifth-line therapies, TAS-102 or regorafenib. These patients don’t make it to even third line. We’re chipping away at what we think is a very homogenous group of peoples’ metastatic disease. They’re obviously not.

DR HENRY In the BRAF-mutant patient, the vemurafenib might drive them toward EGFR, and then the cetuximab could come in and handle that diversion of the pathway. Fascinating.

DR HALLER The preferred regimen in first-line therapy for a BRAF mutant might be FOLFIRI, cetuximab, and vemurafenib, especially on the left side.

DR HENRY Certainly makes sense. We’ll continue the theme at ASCO of “new standard of care.” Let’s move to gastroesophageal junction. There was a so-called FLOT (5-FU, leucovorin, oxaliplatin, Taxotere) presentation in the neoadjuvant/adjuvant setting, 4 cycles preoperatively and 4 cycles postoperatively. Could you comment on that study?

DR HALLER Gastric cancer for metastatic disease has a very large buffet of treatment regimens, and some just become entrenched, like the ECF regimen with epirubicin (epirubicin, cisplatin, 5-FU), where most people don’t exactly know what the contribution of that drug is, and so some people use EOX (epirubicin, oxaliplatin, capecitabine), some people use FOLFOX, some people use FOLFIRI. It gets a little bit confusing as to whether you use taxanes, platinums, or 5-FU or capecitabine.

The Germans came up with a regimen called FLOT – it’s sort of like FOLFOX with Taxotere attached. They did a very large study comparing it with ECF or ECX (epirubicin, cisplatin, capecitabine; Figure 3).⁴ The overall endpoint with over 700 patients was survival. This is an adjuvant regimen. Only 37% of people got ECF or ECX postoperatively, and 50% of the FLOT patients got the regimens postoperatively.

DR HENRY Indeed. Could you comment on the BILCAP study and adjuvant capecitabine for biliary tract cancer?

DR HALLER There are large meta-analyses looking at adjuvant therapy for biliary tract cancers typically from fairly small, fairly old studies that all suggest that in certain stages of resected biliary tumors, either bile duct or gall bladder, adjuvant treatment works, and typically either chemotherapy and radiotherapy, or chemotherapy alone, but not radiotherapy alone.

Capecitabine has been used for metastatic disease for years, mostly by default, and because most GI tumors have some response to fluoropyridines. But we’re finally able now to do large trials in biliary tumors, so this trial was a very large study with almost 450 patients from the United Kingdom over an 8-year period. About 20% were gallbladder, so the R0 surgery was about 60%, R1 at about 40% (Figure 4).⁶

DR HENRY Great data and a small population, but a population in need. That moves us on to pancreatic cancer, and I don’t know if this is happening nationwide, but in my practice, I’m seeing more. These patients tend to present beyond surgery, so they have metastatic or advanced pancreatic cancer. Any comment on where you think this field is going?

DR HALLER We were a bit bereft of new pancreatic cancer studies at ASCO this year. We’re certainly looking more at neoadjuvant therapy for pancreatic cancer, primarily because of ease of administration and the increased ability to tolerate treatments in the preoperative setting. There aren’t many people that get downstaged, but some are. Unfortunately, even in the MSI-high pancreas, which is a small subset, they don’t seem to get as big a bang out of the checkpoint inhibitors as in other tumor sites, so I’m afraid I didn’t come home with much new about this subset of patients.

DR HENRY We’ve covered a nice group of studies and practice-changing new standard-of-care comments from ASCO and other studies. Thank Dr Dan Haller for being with us and commenting. This podcast and discussion are brought to you from The Journal of Community and Supportive Oncology, the JCSO. I’m Dr David Henry, and you can listen to this and other archived articles or podcasts at JCSO-online.com. Thanks for listening.

DR HENRY I am Dr David Henry, the Editor-in-Chief of The Journal of Community and Supportive Oncology (JCSO; JCSO-online.com). I’m with Dr Dan Haller, former Editor-in-Chief of the Journal of Clinical Oncology and currently the Editor-in-Chief of American Society of Clinical Oncology (ASCO) University. He is also my friend and former mentor at University of Pennsylvania Abramson Cancer Center, where he is Professor Emeritus. We’re going to talk about colorectal cancer and a lot of things that came out of the ASCO meeting this year that were practice changing, or certainly interesting and worth further discussion. I thought we’d start talking about the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration, in which for patients with colorectal cancer who were considering adjuvant postoperative therapy, there was a discussion of 3 cycles versus 6 cycles of FOLFOX (fluorouracil [5-FU] plus oxaliplatin) or XELOX (capecitabine plus oxaliplatin, also CAPOX) (Figure 1).¹ Could you comment on what they did, and how that study turned out?

Three of them were individually reported at ASCO this year, and then the totality was presented at the plenary session – the first time in 12 years that a gastrointestinal (GI) cancer trial made the plenary session. The whole point, obviously, is neuropathy. With 6 months of FOLFOX or XELOX, about 13% or more patients will develop grade 3 neuropathy, even if people stop short of the full-cycle length, and that is a big deal for the 50,000 patients or so who get adjuvant therapy. At the plenary session, the data were presented and the next day three individual trials were presented and discussed by Jeff Meyerhardt (of Dana-Farber Cancer Institute, Boston).

There were 6 different trials: a few included rectum, some included stage II, some used CAPOX and FOLFOX-4 or 6. The only trial that used only FOLFOX was the Cancer and Leukemia Group B (CALGB) trial in the United States (US). There was a lot of heterogeneity, but when Dan was around, I asked him whether that was a problem, and he said on the contrary, was a better thing because it allowed for real-life practice.

The primary endpoint of the study was to look for noninferiority of 3 months versus 6 months of treatment. The noninferiority margin was at a hazard ratio of 1.12, so they were willing to barter down a few percentage points from benefit. If you looked at the primary disease-free survival analysis, the hazard ratio was 1.07, which was an absolute difference of 0.9%, favoring 3 months of therapy. But because the hazard ratio crossed the 1.12 boundary, it was considered inconclusive and not proven.

If you looked at the regimens, CAPOX outperformed FOLFOX. That’s a regimen we don’t do much in the US. We tend to use more FOLFOX, but CAPOX looked better. What they then did was look at the different subsets of patients, and the subsets that it was obviously as good in was the group that had T1-3N1 disease, where 3 months of therapy was clearly just as good as 6 months of therapy, with only a 3% risk of grade 3 neuropathy.
 

DR HENRY That would be one to three nodes?

DR HALLER Exactly. That’s about 50% of patients. In the T4N2 patients, neither regimen did very well and the 3-year disease-free survival was in the range of 50%, which is clearly unacceptable. Jeff discussed two things. Why could CAPOX be better? If you do the math, when you do CAPOX, you get more oxaliplatin during the first few months of therapy, because it’s 130 mg every 3 weeks, rather than 85 mg every 2 weeks. His conclusion was, “for my next patient who has T4N2 disease, I’ll offer 6 months of FOLFOX.” The study that really needs to be done in these patients is FOLFOX versus FOLFIRINOX (folinic acid, 5-FU, irinotecan, oxaliplatin) or FOLFOXIRI (folinic acid, 5-FU, oxaliplatin, irinotecan), because we’re clearly not doing well with this population of patients. But for the T1-3N1 disease, discuss the toxicities and logistics of CAPOX or FOLFOX with the patient. They’ll probably offer 3 months of CAPOX.

He discussed the two new trials. One is a study called ARGO, which is being done by the National Surgical Adjuvant Breast and Bowel Project, where people get standard adjuvant chemotherapy, and they’re then randomized to either 24 months of regorafenib 120 mg per day or a placebo. This is an attempt to recreate the transient benefit from bevacizumab in the NSABP C-08 trial. It’s accruing slowly because regorafenib has some toxicity associated with it, but it probably will be completed. Will it continue the benefit as seen in the 12 months of bevacizumab and C-08? We’ll see.

The other, more interesting study is being done in the cooperative groups looking at FOLFOX plus atezolizumab, one of the checkpoint inhibitors. The difficulty here is that only 15% of people with stage III disease have microsatellite instability (MSI)-high tumors, but it’s certainly compelling. This is a straight up comparison. It’s 6 months of FOLFOX in the control arm, or 6 months of FOLFOX plus atezolizumab concurrently for 6 months, and then an additional 6 months of atezolizumab. These are both very fascinating ideas.
 

DR HENRY To go back to one of your original points, this 3 versus 6 months: the neuropathy is significantly less in those getting the 3 months?
 

DR HALLER It went to 3%.
 

DR HENRY We all see that is very bothersome to patients. Before we leave colorectal, I must ask about the right-sided versus left-sided colorectal cancer that we hear a lot about now. Could you comment on how right-sided is worse than left-sided, and do we understand why?

DR HALLER There are two things to consider. If you look back even to simple trials of 5-FU or biochemical modulated 5-FU from 20 years ago, there were clear differences showing worse prognosis in patients with right-sided tumors, so that’s one point to be made. It’s been consistently seen but never acted upon. Then, the explanation for it, possibly, is that the right colon and left colon are two biologically different organs – and they are. Embryologically, the right colon comes from the midgut and the left colon comes from the hindgut, and there were several presentations at ASCO and at prior meetings showing that when you look at different mutations, they differ between the right and left colons. The right-sided tumors are more MSI-high and more BRAF-mutated, left-sided mutations less so.

Then, people started analyzing many of the very large colon cancer trials, including the US trial CALB/SWOG C80405 and the FIRE-3 trials in Europe, where backbone chemotherapy of FOLFIRI or FOLFOX was given with either cetuximab or bevacizumab in RAS wild-type patients. For one study, C80405, they saw that for cetuximab, on the right side, the median survival was 16.7 months and on the left side, it’s 36 months – a 20-month difference. In fact, if you look at the totality of the data, 16.7 almost looks like cetuximab is harming them, as if you were giving it to a RAS-mutated patient, but they were not. They were all RAS wild-type.

For bevacizumab, the right side was 24 months; the left side was 31.4 months. If you look at the left, cetuximab was 36 months and bevacizumab was 31.4 months, so it appears left-sided tumors should get more cetuximab than they are now getting in the US with a 5-month difference, but that decrement is much different on the right, where there’s an 8-month benefit for bevacizumab compared with cetuximab. There is a very good review by Dirk Arnold, who looked at a totality of 6 studies to really examine this more carefully.²

The National Comprehensive Cancer Network has chimed in on this, and is suggesting that for the 25% of people who have right-sided tumors, epidermal growth factor receptor (EGFR) agents not be considered in first-line therapy. NCCN did not go as far to say that EGFR agents should be given on the left side. As I said, the differences are much more impressive in the right, so this is a real sea change for people to consider which side of the tumor affects outcome.

Deb Schrag (Dana-Farber Cancer Institute) presented data at last year’s ASCO not only for stage IV disease showing the same thing, but also stage III disease where there are also right-versus-left differences in terms of recurrence, with a hazard ratio on the right side of about 1.4 compared with the left-sided tumors. Maybe it should be true that 3 months is especially good if you’re treating left-sided tumors, and maybe the right-sided tumor needs to be also calculated with the factors we just talked about. These are two big changes in an area in which we literally haven’t made any change since FOLFOX was introduced a decade ago.

DR HENRY That’s really fascinating, and if not practice changing, then practice challenging. Staying with the mutations idea, in my patients, I’m checking the RAS family and the BRAF mutation, where I’ve learned that’s a particularly bad mutation. I wonder if you might comment on the Kopetz trial, which took a cohort of BRAF mutants and treated them (Figure 2).3 How did that turn out?

DR HALLER It turned out well. We’re turning colon cancer into non–small cell lung cancer in that we’re getting small groups of patients who now have very dedicated care. The backstory here is that there was some thought that you should be treating mutations, not tumor sites. Drugs such as vemurafenib, for example, which is a BRAF inhibitor, worked well in melanoma for the same mutation that’s in colon cancer, V600E. But when vemurafenib was used in the BRAF-mutant patients – these are 10% of the population – median survivorship was one-third that of the rest of the patients, so roughly 12 months. People looked like they were doing worse when vemurafenib was used. They had no benefit.

Scott Kopetz at MD Anderson (Houston, Texas) is a very good bench-to-bed-and-back sort of doc. He looked at this in cell lines and found that when you give a BRAF inhibitor, you upregulate EGFR so you add an EGFR inhibitor. He did a phase 1 and 1B study, and then in the co-operative groups, a study was done – a randomized phase 2 trial for people who had the BRAF-V600E mutation failing first-line therapy, and then went on to receive either irinotecan single agent or irinotecan plus cetuximab or a triple arm of irinotecan, cetuximab, and vemurafenib. There was a crossover, and so the primary endpoint was progression-free survival. It accrued rapidly.

Again, small study, about 100 patients, but for the double-agent arm, or cetuximab–irinotecan, the median survivorship was 2 months. It was 4.4 months for the combination, so more than double. The response rate quadrupled from 4% to 16%, and the people who had disease control tripled, from 22% to 67%. Many of these patients had bulky disease, BRAF mutations. They need response, so this is a very important endpoint.

Overall survival was not different, in part because it was a crossover, and the crossover patients did pretty well. This is going to move more toward first-line therapy, because we don’t talk about fourth- and fifth-line therapies, TAS-102 or regorafenib. These patients don’t make it to even third line. We’re chipping away at what we think is a very homogenous group of peoples’ metastatic disease. They’re obviously not.

DR HENRY In the BRAF-mutant patient, the vemurafenib might drive them toward EGFR, and then the cetuximab could come in and handle that diversion of the pathway. Fascinating.

DR HALLER The preferred regimen in first-line therapy for a BRAF mutant might be FOLFIRI, cetuximab, and vemurafenib, especially on the left side.

DR HENRY Certainly makes sense. We’ll continue the theme at ASCO of “new standard of care.” Let’s move to gastroesophageal junction. There was a so-called FLOT (5-FU, leucovorin, oxaliplatin, Taxotere) presentation in the neoadjuvant/adjuvant setting, 4 cycles preoperatively and 4 cycles postoperatively. Could you comment on that study?

DR HALLER Gastric cancer for metastatic disease has a very large buffet of treatment regimens, and some just become entrenched, like the ECF regimen with epirubicin (epirubicin, cisplatin, 5-FU), where most people don’t exactly know what the contribution of that drug is, and so some people use EOX (epirubicin, oxaliplatin, capecitabine), some people use FOLFOX, some people use FOLFIRI. It gets a little bit confusing as to whether you use taxanes, platinums, or 5-FU or capecitabine.

The Germans came up with a regimen called FLOT – it’s sort of like FOLFOX with Taxotere attached. They did a very large study comparing it with ECF or ECX (epirubicin, cisplatin, capecitabine; Figure 3).⁴ The overall endpoint with over 700 patients was survival. This is an adjuvant regimen. Only 37% of people got ECF or ECX postoperatively, and 50% of the FLOT patients got the regimens postoperatively.

DR HENRY Indeed. Could you comment on the BILCAP study and adjuvant capecitabine for biliary tract cancer?

DR HALLER There are large meta-analyses looking at adjuvant therapy for biliary tract cancers typically from fairly small, fairly old studies that all suggest that in certain stages of resected biliary tumors, either bile duct or gall bladder, adjuvant treatment works, and typically either chemotherapy and radiotherapy, or chemotherapy alone, but not radiotherapy alone.

Capecitabine has been used for metastatic disease for years, mostly by default, and because most GI tumors have some response to fluoropyridines. But we’re finally able now to do large trials in biliary tumors, so this trial was a very large study with almost 450 patients from the United Kingdom over an 8-year period. About 20% were gallbladder, so the R0 surgery was about 60%, R1 at about 40% (Figure 4).⁶

DR HENRY Great data and a small population, but a population in need. That moves us on to pancreatic cancer, and I don’t know if this is happening nationwide, but in my practice, I’m seeing more. These patients tend to present beyond surgery, so they have metastatic or advanced pancreatic cancer. Any comment on where you think this field is going?

DR HALLER We were a bit bereft of new pancreatic cancer studies at ASCO this year. We’re certainly looking more at neoadjuvant therapy for pancreatic cancer, primarily because of ease of administration and the increased ability to tolerate treatments in the preoperative setting. There aren’t many people that get downstaged, but some are. Unfortunately, even in the MSI-high pancreas, which is a small subset, they don’t seem to get as big a bang out of the checkpoint inhibitors as in other tumor sites, so I’m afraid I didn’t come home with much new about this subset of patients.

DR HENRY We’ve covered a nice group of studies and practice-changing new standard-of-care comments from ASCO and other studies. Thank Dr Dan Haller for being with us and commenting. This podcast and discussion are brought to you from The Journal of Community and Supportive Oncology, the JCSO. I’m Dr David Henry, and you can listen to this and other archived articles or podcasts at JCSO-online.com. Thanks for listening.

DR HENRY I am Dr David Henry, the Editor-in-Chief of The Journal of Community and Supportive Oncology (JCSO; JCSO-online.com). I’m with Dr Dan Haller, former Editor-in-Chief of the Journal of Clinical Oncology and currently the Editor-in-Chief of American Society of Clinical Oncology (ASCO) University. He is also my friend and former mentor at University of Pennsylvania Abramson Cancer Center, where he is Professor Emeritus. We’re going to talk about colorectal cancer and a lot of things that came out of the ASCO meeting this year that were practice changing, or certainly interesting and worth further discussion. I thought we’d start talking about the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration, in which for patients with colorectal cancer who were considering adjuvant postoperative therapy, there was a discussion of 3 cycles versus 6 cycles of FOLFOX (fluorouracil [5-FU] plus oxaliplatin) or XELOX (capecitabine plus oxaliplatin, also CAPOX) (Figure 1).¹ Could you comment on what they did, and how that study turned out?

Three of them were individually reported at ASCO this year, and then the totality was presented at the plenary session – the first time in 12 years that a gastrointestinal (GI) cancer trial made the plenary session. The whole point, obviously, is neuropathy. With 6 months of FOLFOX or XELOX, about 13% or more patients will develop grade 3 neuropathy, even if people stop short of the full-cycle length, and that is a big deal for the 50,000 patients or so who get adjuvant therapy. At the plenary session, the data were presented and the next day three individual trials were presented and discussed by Jeff Meyerhardt (of Dana-Farber Cancer Institute, Boston).

There were 6 different trials: a few included rectum, some included stage II, some used CAPOX and FOLFOX-4 or 6. The only trial that used only FOLFOX was the Cancer and Leukemia Group B (CALGB) trial in the United States (US). There was a lot of heterogeneity, but when Dan was around, I asked him whether that was a problem, and he said on the contrary, was a better thing because it allowed for real-life practice.

The primary endpoint of the study was to look for noninferiority of 3 months versus 6 months of treatment. The noninferiority margin was at a hazard ratio of 1.12, so they were willing to barter down a few percentage points from benefit. If you looked at the primary disease-free survival analysis, the hazard ratio was 1.07, which was an absolute difference of 0.9%, favoring 3 months of therapy. But because the hazard ratio crossed the 1.12 boundary, it was considered inconclusive and not proven.

If you looked at the regimens, CAPOX outperformed FOLFOX. That’s a regimen we don’t do much in the US. We tend to use more FOLFOX, but CAPOX looked better. What they then did was look at the different subsets of patients, and the subsets that it was obviously as good in was the group that had T1-3N1 disease, where 3 months of therapy was clearly just as good as 6 months of therapy, with only a 3% risk of grade 3 neuropathy.
 

DR HENRY That would be one to three nodes?

DR HALLER Exactly. That’s about 50% of patients. In the T4N2 patients, neither regimen did very well and the 3-year disease-free survival was in the range of 50%, which is clearly unacceptable. Jeff discussed two things. Why could CAPOX be better? If you do the math, when you do CAPOX, you get more oxaliplatin during the first few months of therapy, because it’s 130 mg every 3 weeks, rather than 85 mg every 2 weeks. His conclusion was, “for my next patient who has T4N2 disease, I’ll offer 6 months of FOLFOX.” The study that really needs to be done in these patients is FOLFOX versus FOLFIRINOX (folinic acid, 5-FU, irinotecan, oxaliplatin) or FOLFOXIRI (folinic acid, 5-FU, oxaliplatin, irinotecan), because we’re clearly not doing well with this population of patients. But for the T1-3N1 disease, discuss the toxicities and logistics of CAPOX or FOLFOX with the patient. They’ll probably offer 3 months of CAPOX.

He discussed the two new trials. One is a study called ARGO, which is being done by the National Surgical Adjuvant Breast and Bowel Project, where people get standard adjuvant chemotherapy, and they’re then randomized to either 24 months of regorafenib 120 mg per day or a placebo. This is an attempt to recreate the transient benefit from bevacizumab in the NSABP C-08 trial. It’s accruing slowly because regorafenib has some toxicity associated with it, but it probably will be completed. Will it continue the benefit as seen in the 12 months of bevacizumab and C-08? We’ll see.

The other, more interesting study is being done in the cooperative groups looking at FOLFOX plus atezolizumab, one of the checkpoint inhibitors. The difficulty here is that only 15% of people with stage III disease have microsatellite instability (MSI)-high tumors, but it’s certainly compelling. This is a straight up comparison. It’s 6 months of FOLFOX in the control arm, or 6 months of FOLFOX plus atezolizumab concurrently for 6 months, and then an additional 6 months of atezolizumab. These are both very fascinating ideas.
 

DR HENRY To go back to one of your original points, this 3 versus 6 months: the neuropathy is significantly less in those getting the 3 months?
 

DR HALLER It went to 3%.
 

DR HENRY We all see that is very bothersome to patients. Before we leave colorectal, I must ask about the right-sided versus left-sided colorectal cancer that we hear a lot about now. Could you comment on how right-sided is worse than left-sided, and do we understand why?

DR HALLER There are two things to consider. If you look back even to simple trials of 5-FU or biochemical modulated 5-FU from 20 years ago, there were clear differences showing worse prognosis in patients with right-sided tumors, so that’s one point to be made. It’s been consistently seen but never acted upon. Then, the explanation for it, possibly, is that the right colon and left colon are two biologically different organs – and they are. Embryologically, the right colon comes from the midgut and the left colon comes from the hindgut, and there were several presentations at ASCO and at prior meetings showing that when you look at different mutations, they differ between the right and left colons. The right-sided tumors are more MSI-high and more BRAF-mutated, left-sided mutations less so.

Then, people started analyzing many of the very large colon cancer trials, including the US trial CALB/SWOG C80405 and the FIRE-3 trials in Europe, where backbone chemotherapy of FOLFIRI or FOLFOX was given with either cetuximab or bevacizumab in RAS wild-type patients. For one study, C80405, they saw that for cetuximab, on the right side, the median survival was 16.7 months and on the left side, it’s 36 months – a 20-month difference. In fact, if you look at the totality of the data, 16.7 almost looks like cetuximab is harming them, as if you were giving it to a RAS-mutated patient, but they were not. They were all RAS wild-type.

For bevacizumab, the right side was 24 months; the left side was 31.4 months. If you look at the left, cetuximab was 36 months and bevacizumab was 31.4 months, so it appears left-sided tumors should get more cetuximab than they are now getting in the US with a 5-month difference, but that decrement is much different on the right, where there’s an 8-month benefit for bevacizumab compared with cetuximab. There is a very good review by Dirk Arnold, who looked at a totality of 6 studies to really examine this more carefully.²

The National Comprehensive Cancer Network has chimed in on this, and is suggesting that for the 25% of people who have right-sided tumors, epidermal growth factor receptor (EGFR) agents not be considered in first-line therapy. NCCN did not go as far to say that EGFR agents should be given on the left side. As I said, the differences are much more impressive in the right, so this is a real sea change for people to consider which side of the tumor affects outcome.

Deb Schrag (Dana-Farber Cancer Institute) presented data at last year’s ASCO not only for stage IV disease showing the same thing, but also stage III disease where there are also right-versus-left differences in terms of recurrence, with a hazard ratio on the right side of about 1.4 compared with the left-sided tumors. Maybe it should be true that 3 months is especially good if you’re treating left-sided tumors, and maybe the right-sided tumor needs to be also calculated with the factors we just talked about. These are two big changes in an area in which we literally haven’t made any change since FOLFOX was introduced a decade ago.

DR HENRY That’s really fascinating, and if not practice changing, then practice challenging. Staying with the mutations idea, in my patients, I’m checking the RAS family and the BRAF mutation, where I’ve learned that’s a particularly bad mutation. I wonder if you might comment on the Kopetz trial, which took a cohort of BRAF mutants and treated them (Figure 2).3 How did that turn out?

DR HALLER It turned out well. We’re turning colon cancer into non–small cell lung cancer in that we’re getting small groups of patients who now have very dedicated care. The backstory here is that there was some thought that you should be treating mutations, not tumor sites. Drugs such as vemurafenib, for example, which is a BRAF inhibitor, worked well in melanoma for the same mutation that’s in colon cancer, V600E. But when vemurafenib was used in the BRAF-mutant patients – these are 10% of the population – median survivorship was one-third that of the rest of the patients, so roughly 12 months. People looked like they were doing worse when vemurafenib was used. They had no benefit.

Scott Kopetz at MD Anderson (Houston, Texas) is a very good bench-to-bed-and-back sort of doc. He looked at this in cell lines and found that when you give a BRAF inhibitor, you upregulate EGFR so you add an EGFR inhibitor. He did a phase 1 and 1B study, and then in the co-operative groups, a study was done – a randomized phase 2 trial for people who had the BRAF-V600E mutation failing first-line therapy, and then went on to receive either irinotecan single agent or irinotecan plus cetuximab or a triple arm of irinotecan, cetuximab, and vemurafenib. There was a crossover, and so the primary endpoint was progression-free survival. It accrued rapidly.

Again, small study, about 100 patients, but for the double-agent arm, or cetuximab–irinotecan, the median survivorship was 2 months. It was 4.4 months for the combination, so more than double. The response rate quadrupled from 4% to 16%, and the people who had disease control tripled, from 22% to 67%. Many of these patients had bulky disease, BRAF mutations. They need response, so this is a very important endpoint.

Overall survival was not different, in part because it was a crossover, and the crossover patients did pretty well. This is going to move more toward first-line therapy, because we don’t talk about fourth- and fifth-line therapies, TAS-102 or regorafenib. These patients don’t make it to even third line. We’re chipping away at what we think is a very homogenous group of peoples’ metastatic disease. They’re obviously not.

DR HENRY In the BRAF-mutant patient, the vemurafenib might drive them toward EGFR, and then the cetuximab could come in and handle that diversion of the pathway. Fascinating.

DR HALLER The preferred regimen in first-line therapy for a BRAF mutant might be FOLFIRI, cetuximab, and vemurafenib, especially on the left side.

DR HENRY Certainly makes sense. We’ll continue the theme at ASCO of “new standard of care.” Let’s move to gastroesophageal junction. There was a so-called FLOT (5-FU, leucovorin, oxaliplatin, Taxotere) presentation in the neoadjuvant/adjuvant setting, 4 cycles preoperatively and 4 cycles postoperatively. Could you comment on that study?

DR HALLER Gastric cancer for metastatic disease has a very large buffet of treatment regimens, and some just become entrenched, like the ECF regimen with epirubicin (epirubicin, cisplatin, 5-FU), where most people don’t exactly know what the contribution of that drug is, and so some people use EOX (epirubicin, oxaliplatin, capecitabine), some people use FOLFOX, some people use FOLFIRI. It gets a little bit confusing as to whether you use taxanes, platinums, or 5-FU or capecitabine.

The Germans came up with a regimen called FLOT – it’s sort of like FOLFOX with Taxotere attached. They did a very large study comparing it with ECF or ECX (epirubicin, cisplatin, capecitabine; Figure 3).⁴ The overall endpoint with over 700 patients was survival. This is an adjuvant regimen. Only 37% of people got ECF or ECX postoperatively, and 50% of the FLOT patients got the regimens postoperatively.

DR HENRY Indeed. Could you comment on the BILCAP study and adjuvant capecitabine for biliary tract cancer?

DR HALLER There are large meta-analyses looking at adjuvant therapy for biliary tract cancers typically from fairly small, fairly old studies that all suggest that in certain stages of resected biliary tumors, either bile duct or gall bladder, adjuvant treatment works, and typically either chemotherapy and radiotherapy, or chemotherapy alone, but not radiotherapy alone.

Capecitabine has been used for metastatic disease for years, mostly by default, and because most GI tumors have some response to fluoropyridines. But we’re finally able now to do large trials in biliary tumors, so this trial was a very large study with almost 450 patients from the United Kingdom over an 8-year period. About 20% were gallbladder, so the R0 surgery was about 60%, R1 at about 40% (Figure 4).⁶

DR HENRY Great data and a small population, but a population in need. That moves us on to pancreatic cancer, and I don’t know if this is happening nationwide, but in my practice, I’m seeing more. These patients tend to present beyond surgery, so they have metastatic or advanced pancreatic cancer. Any comment on where you think this field is going?

DR HALLER We were a bit bereft of new pancreatic cancer studies at ASCO this year. We’re certainly looking more at neoadjuvant therapy for pancreatic cancer, primarily because of ease of administration and the increased ability to tolerate treatments in the preoperative setting. There aren’t many people that get downstaged, but some are. Unfortunately, even in the MSI-high pancreas, which is a small subset, they don’t seem to get as big a bang out of the checkpoint inhibitors as in other tumor sites, so I’m afraid I didn’t come home with much new about this subset of patients.

DR HENRY We’ve covered a nice group of studies and practice-changing new standard-of-care comments from ASCO and other studies. Thank Dr Dan Haller for being with us and commenting. This podcast and discussion are brought to you from The Journal of Community and Supportive Oncology, the JCSO. I’m Dr David Henry, and you can listen to this and other archived articles or podcasts at JCSO-online.com. Thanks for listening.

Women with relapsing-remitting multiple sclerosis (MS) who discontinue natalizumab treatment before pregnancy may have increased disease activity, according to a study published March 6 in Neurology. In addition, taking natalizumab during the first trimester of pregnancy increases the risk of miscarriage, although the risk remains similar to that of the general population, according to an accompanying study.

An Analysis of Pregnancy Data

Emilio Portaccio, MD, of the Don Carlo Gnocchi Foundation in Florence, Italy, and colleagues analyzed data for all pregnancies between 2009 and 2015 in patients with MS who presented to 19 Italian sites. They compared data for 83 patients receiving natalizumab with those for 350 control patients who were receiving injectable immunomodulatory agents or no treatment. The investigators followed up with the women every six months, at each relapse, and at one year after birth.

The patients receiving natalizumab had 92 pregnancies. Approximately 37% of women receiving natalizumab had at least one relapse during pregnancy, compared with 10% of controls. Relapse rate during pregnancy was higher among patients whose last infusion occurred before the last menstrual period (55.9%) than among patients whose last infusion occurred after the last menstrual period (20%) or controls (10%). Receiving the last natalizumab infusion before the last menstrual period was the only predictor of relapse during pregnancy. In the first trimester after delivery, the rate of relapse was 21.7% in natalizumab-treated patients and 13.7% in controls.

Twelve patients had disability worsening at the end of the one-year follow-up. In 11 of these patients, disability accumulation resulted from relapses during pregnancy or after delivery. Disease progression was reduced in patients for whom medication was reintroduced earlier after delivery.

About 75% of pregnancies in women receiving natalizumab had treatment exposure, and the mean duration of exposure was 1.2 weeks. The odds ratio of spontaneous abortion was 3.9 among patients receiving natalizumab, compared with controls. The rate of spontaneous abortion among natalizumab-treated patients (17.4%) was similar to that observed for the general Italian population (14%), however. The rate of major congenital anomalies was 3.7% in patients exposed to natalizumab, 1.3% in patients exposed to interferon beta, and 0.9% in untreated patients. The differences between groups were not significant. Exposure to natalizumab and exposure to interferon beta were associated with a lower length of the newborn.

Relapse Severity Was Not Measured

One limitation of the studies is that the women treated with natalizumab may have been different from women not treated with natalizumab in ways that the investigators did not measure. In addition, the researchers did not measure relapse severity.

“Our findings suggest that if women who take natalizumab for MS want to become pregnant, it may be best to continue treatment up until a pregnancy test is positive and then at that point discontinue use,” said Dr. Portaccio. “While there is still a risk of increased disease activity, this course of action may lower that risk.”

—Erik Greb

Suggested Reading

Portaccio E, Annovazzi P, Ghezzi A, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: Fetal risks. Neurology. 2018;90(10):e823-e831.

Portaccio E, Moiola L, Martinelli V, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Neurology. 2018;90(10):e832-e839.

Women with relapsing-remitting multiple sclerosis (MS) who discontinue natalizumab treatment before pregnancy may have increased disease activity, according to a study published March 6 in Neurology. In addition, taking natalizumab during the first trimester of pregnancy increases the risk of miscarriage, although the risk remains similar to that of the general population, according to an accompanying study.

An Analysis of Pregnancy Data

Emilio Portaccio, MD, of the Don Carlo Gnocchi Foundation in Florence, Italy, and colleagues analyzed data for all pregnancies between 2009 and 2015 in patients with MS who presented to 19 Italian sites. They compared data for 83 patients receiving natalizumab with those for 350 control patients who were receiving injectable immunomodulatory agents or no treatment. The investigators followed up with the women every six months, at each relapse, and at one year after birth.

The patients receiving natalizumab had 92 pregnancies. Approximately 37% of women receiving natalizumab had at least one relapse during pregnancy, compared with 10% of controls. Relapse rate during pregnancy was higher among patients whose last infusion occurred before the last menstrual period (55.9%) than among patients whose last infusion occurred after the last menstrual period (20%) or controls (10%). Receiving the last natalizumab infusion before the last menstrual period was the only predictor of relapse during pregnancy. In the first trimester after delivery, the rate of relapse was 21.7% in natalizumab-treated patients and 13.7% in controls.

Twelve patients had disability worsening at the end of the one-year follow-up. In 11 of these patients, disability accumulation resulted from relapses during pregnancy or after delivery. Disease progression was reduced in patients for whom medication was reintroduced earlier after delivery.

About 75% of pregnancies in women receiving natalizumab had treatment exposure, and the mean duration of exposure was 1.2 weeks. The odds ratio of spontaneous abortion was 3.9 among patients receiving natalizumab, compared with controls. The rate of spontaneous abortion among natalizumab-treated patients (17.4%) was similar to that observed for the general Italian population (14%), however. The rate of major congenital anomalies was 3.7% in patients exposed to natalizumab, 1.3% in patients exposed to interferon beta, and 0.9% in untreated patients. The differences between groups were not significant. Exposure to natalizumab and exposure to interferon beta were associated with a lower length of the newborn.

Relapse Severity Was Not Measured

One limitation of the studies is that the women treated with natalizumab may have been different from women not treated with natalizumab in ways that the investigators did not measure. In addition, the researchers did not measure relapse severity.

“Our findings suggest that if women who take natalizumab for MS want to become pregnant, it may be best to continue treatment up until a pregnancy test is positive and then at that point discontinue use,” said Dr. Portaccio. “While there is still a risk of increased disease activity, this course of action may lower that risk.”

—Erik Greb

Suggested Reading

Portaccio E, Annovazzi P, Ghezzi A, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: Fetal risks. Neurology. 2018;90(10):e823-e831.

Portaccio E, Moiola L, Martinelli V, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Neurology. 2018;90(10):e832-e839.

Women with relapsing-remitting multiple sclerosis (MS) who discontinue natalizumab treatment before pregnancy may have increased disease activity, according to a study published March 6 in Neurology. In addition, taking natalizumab during the first trimester of pregnancy increases the risk of miscarriage, although the risk remains similar to that of the general population, according to an accompanying study.

An Analysis of Pregnancy Data

Emilio Portaccio, MD, of the Don Carlo Gnocchi Foundation in Florence, Italy, and colleagues analyzed data for all pregnancies between 2009 and 2015 in patients with MS who presented to 19 Italian sites. They compared data for 83 patients receiving natalizumab with those for 350 control patients who were receiving injectable immunomodulatory agents or no treatment. The investigators followed up with the women every six months, at each relapse, and at one year after birth.

The patients receiving natalizumab had 92 pregnancies. Approximately 37% of women receiving natalizumab had at least one relapse during pregnancy, compared with 10% of controls. Relapse rate during pregnancy was higher among patients whose last infusion occurred before the last menstrual period (55.9%) than among patients whose last infusion occurred after the last menstrual period (20%) or controls (10%). Receiving the last natalizumab infusion before the last menstrual period was the only predictor of relapse during pregnancy. In the first trimester after delivery, the rate of relapse was 21.7% in natalizumab-treated patients and 13.7% in controls.

Twelve patients had disability worsening at the end of the one-year follow-up. In 11 of these patients, disability accumulation resulted from relapses during pregnancy or after delivery. Disease progression was reduced in patients for whom medication was reintroduced earlier after delivery.

About 75% of pregnancies in women receiving natalizumab had treatment exposure, and the mean duration of exposure was 1.2 weeks. The odds ratio of spontaneous abortion was 3.9 among patients receiving natalizumab, compared with controls. The rate of spontaneous abortion among natalizumab-treated patients (17.4%) was similar to that observed for the general Italian population (14%), however. The rate of major congenital anomalies was 3.7% in patients exposed to natalizumab, 1.3% in patients exposed to interferon beta, and 0.9% in untreated patients. The differences between groups were not significant. Exposure to natalizumab and exposure to interferon beta were associated with a lower length of the newborn.

Relapse Severity Was Not Measured

One limitation of the studies is that the women treated with natalizumab may have been different from women not treated with natalizumab in ways that the investigators did not measure. In addition, the researchers did not measure relapse severity.

“Our findings suggest that if women who take natalizumab for MS want to become pregnant, it may be best to continue treatment up until a pregnancy test is positive and then at that point discontinue use,” said Dr. Portaccio. “While there is still a risk of increased disease activity, this course of action may lower that risk.”

—Erik Greb

Suggested Reading

Portaccio E, Annovazzi P, Ghezzi A, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: Fetal risks. Neurology. 2018;90(10):e823-e831.

Portaccio E, Moiola L, Martinelli V, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Neurology. 2018;90(10):e832-e839.