SAN DIEGO – What causes multiple sclerosis (MS)? A team of Scottish researchers offers a new theory that it’s triggered in part by a one-two punch of infection with pinworm – a common condition in the United States, especially among children – and the Epstein-Barr virus (EBV).

The theory identifies pinworm as the prime suspect to be the “missing link” that explains why EBV and MS are so tightly connected, said Patrick Kearns, MBChB, a graduate student at Harvard T.H. Chan School of Public Health in Boston.

Dr. Kearns is the lead author of two reports about the possible role of pinworm that were presented at ACTRIMS Forum 2018, which is held by the Americas Committee for Treatment and Research in Multiple Sclerosis. He spoke in an interview.

cnnews@frontlinemedcom.com

SOURCE: Kearns P et al. ACTRIMS Forum 2018, Abstracts LB257 and LB264.

SAN DIEGO – What causes multiple sclerosis (MS)? A team of Scottish researchers offers a new theory that it’s triggered in part by a one-two punch of infection with pinworm – a common condition in the United States, especially among children – and the Epstein-Barr virus (EBV).

The theory identifies pinworm as the prime suspect to be the “missing link” that explains why EBV and MS are so tightly connected, said Patrick Kearns, MBChB, a graduate student at Harvard T.H. Chan School of Public Health in Boston.

Dr. Kearns is the lead author of two reports about the possible role of pinworm that were presented at ACTRIMS Forum 2018, which is held by the Americas Committee for Treatment and Research in Multiple Sclerosis. He spoke in an interview.

cnnews@frontlinemedcom.com

SOURCE: Kearns P et al. ACTRIMS Forum 2018, Abstracts LB257 and LB264.

SAN DIEGO – What causes multiple sclerosis (MS)? A team of Scottish researchers offers a new theory that it’s triggered in part by a one-two punch of infection with pinworm – a common condition in the United States, especially among children – and the Epstein-Barr virus (EBV).

The theory identifies pinworm as the prime suspect to be the “missing link” that explains why EBV and MS are so tightly connected, said Patrick Kearns, MBChB, a graduate student at Harvard T.H. Chan School of Public Health in Boston.

Dr. Kearns is the lead author of two reports about the possible role of pinworm that were presented at ACTRIMS Forum 2018, which is held by the Americas Committee for Treatment and Research in Multiple Sclerosis. He spoke in an interview.

cnnews@frontlinemedcom.com

SOURCE: Kearns P et al. ACTRIMS Forum 2018, Abstracts LB257 and LB264.

The Diagnosis: Granuloma Faciale

A biopsy from a scalp lesion showed an intense mixed inflammatory infiltrate mainly consisting of eosinophils, but lymphocytes, histiocytes, neutrophils, and plasma cells also were present. A grenz zone was observed between the dermal infiltrate and epidermis. Perivascular infiltrates were penetrating vessel walls, and hyalinization of the vessel walls also was seen (Figure 1). Direct immunofluorescence demonstrated IgG positivity on vessel walls (Figure 2). A diagnosis of granuloma faciale with extrafacial lesions was made. Twice daily application of tacrolimus ointment 0.1% was started, but after a 10-month course of treatment, there was no notable difference in the lesions.

Granuloma faciale (GF) is an uncommon benign dermatosis of unknown pathogenesis characterized by erythematous, brown, or violaceous papules, plaques, or nodules. Granuloma faciale lesions can be solitary or multiple as well as disseminated and most often occur on the face. Predilection sites include the nose, periauricular area, cheeks, forehead, eyelids, and ears; however, lesions also have been reported to occur in extrafacial areas such as the trunk, arms, and legs.^1-4 In our patient, multiple plaques were seen on the scalp. Facial lesions usually precede extrafacial lesions, which may present months to several years after the appearance of facial disease; however, according to our patient's history his scalp lesions appeared before the facial lesions.

The differential diagnoses for GF mainly include erythema elevatum diutinum, cutaneous sarcoidosis, cutaneous lymphoma, lupus, basal cell carcinoma, and cutaneous pseudolymphoma.⁵ Diagnosis may be established based on a combination of clinical features and skin biopsy results. On histopathologic examination, small-vessel vasculitis usually is present with an infiltrate predominantly consisting of neutrophils and eosinophils.⁶

It has been suggested that actinic damage plays a role in the etiology of GF.⁷ The pathogenesis is uncertain, but it is thought that immunophenotypic and molecular analysis of the dermal infiltrate in GF reveals that most lymphocytes are clonally expanded and the process is mediated by interferon gamma.⁷ Tacrolimus acts by binding and inactivating calcineurin and thus blocking T-cell activation and proliferation, so it is not surprising that topical tacrolimus has been shown to be useful in the management of this condition.⁸

The Diagnosis: Granuloma Faciale

A biopsy from a scalp lesion showed an intense mixed inflammatory infiltrate mainly consisting of eosinophils, but lymphocytes, histiocytes, neutrophils, and plasma cells also were present. A grenz zone was observed between the dermal infiltrate and epidermis. Perivascular infiltrates were penetrating vessel walls, and hyalinization of the vessel walls also was seen (Figure 1). Direct immunofluorescence demonstrated IgG positivity on vessel walls (Figure 2). A diagnosis of granuloma faciale with extrafacial lesions was made. Twice daily application of tacrolimus ointment 0.1% was started, but after a 10-month course of treatment, there was no notable difference in the lesions.

Granuloma faciale (GF) is an uncommon benign dermatosis of unknown pathogenesis characterized by erythematous, brown, or violaceous papules, plaques, or nodules. Granuloma faciale lesions can be solitary or multiple as well as disseminated and most often occur on the face. Predilection sites include the nose, periauricular area, cheeks, forehead, eyelids, and ears; however, lesions also have been reported to occur in extrafacial areas such as the trunk, arms, and legs.^1-4 In our patient, multiple plaques were seen on the scalp. Facial lesions usually precede extrafacial lesions, which may present months to several years after the appearance of facial disease; however, according to our patient's history his scalp lesions appeared before the facial lesions.

The differential diagnoses for GF mainly include erythema elevatum diutinum, cutaneous sarcoidosis, cutaneous lymphoma, lupus, basal cell carcinoma, and cutaneous pseudolymphoma.⁵ Diagnosis may be established based on a combination of clinical features and skin biopsy results. On histopathologic examination, small-vessel vasculitis usually is present with an infiltrate predominantly consisting of neutrophils and eosinophils.⁶

It has been suggested that actinic damage plays a role in the etiology of GF.⁷ The pathogenesis is uncertain, but it is thought that immunophenotypic and molecular analysis of the dermal infiltrate in GF reveals that most lymphocytes are clonally expanded and the process is mediated by interferon gamma.⁷ Tacrolimus acts by binding and inactivating calcineurin and thus blocking T-cell activation and proliferation, so it is not surprising that topical tacrolimus has been shown to be useful in the management of this condition.⁸

The Diagnosis: Granuloma Faciale

A biopsy from a scalp lesion showed an intense mixed inflammatory infiltrate mainly consisting of eosinophils, but lymphocytes, histiocytes, neutrophils, and plasma cells also were present. A grenz zone was observed between the dermal infiltrate and epidermis. Perivascular infiltrates were penetrating vessel walls, and hyalinization of the vessel walls also was seen (Figure 1). Direct immunofluorescence demonstrated IgG positivity on vessel walls (Figure 2). A diagnosis of granuloma faciale with extrafacial lesions was made. Twice daily application of tacrolimus ointment 0.1% was started, but after a 10-month course of treatment, there was no notable difference in the lesions.

Granuloma faciale (GF) is an uncommon benign dermatosis of unknown pathogenesis characterized by erythematous, brown, or violaceous papules, plaques, or nodules. Granuloma faciale lesions can be solitary or multiple as well as disseminated and most often occur on the face. Predilection sites include the nose, periauricular area, cheeks, forehead, eyelids, and ears; however, lesions also have been reported to occur in extrafacial areas such as the trunk, arms, and legs.^1-4 In our patient, multiple plaques were seen on the scalp. Facial lesions usually precede extrafacial lesions, which may present months to several years after the appearance of facial disease; however, according to our patient's history his scalp lesions appeared before the facial lesions.

The differential diagnoses for GF mainly include erythema elevatum diutinum, cutaneous sarcoidosis, cutaneous lymphoma, lupus, basal cell carcinoma, and cutaneous pseudolymphoma.⁵ Diagnosis may be established based on a combination of clinical features and skin biopsy results. On histopathologic examination, small-vessel vasculitis usually is present with an infiltrate predominantly consisting of neutrophils and eosinophils.⁶

It has been suggested that actinic damage plays a role in the etiology of GF.⁷ The pathogenesis is uncertain, but it is thought that immunophenotypic and molecular analysis of the dermal infiltrate in GF reveals that most lymphocytes are clonally expanded and the process is mediated by interferon gamma.⁷ Tacrolimus acts by binding and inactivating calcineurin and thus blocking T-cell activation and proliferation, so it is not surprising that topical tacrolimus has been shown to be useful in the management of this condition.⁸

Each year, more than 2.2 million patients in the United States undergo evaluations for symptoms of hemorrhoids, according to updated guidelines on the management of hemorrhoids issued by the American Society of Colon and Rectal Surgeons.

“As a result, it is important to identify symptomatic hemorrhoids as the underlying source of the anorectal symptom and to have a clear understanding of the evaluation and management of this disease process,” wrote Bradley R. Davis, MD, FACS, chief of colon and rectal surgery at the Carolinas Medical Center, Charlotte, N.C., and the fellow members of the Clinical Practice Guidelines Committee of the ASCRS.

Dmitrii Kotin/Thinkstock.com

acssurgerynews@frontlinemedcom.com

SOURCE: Davis BR et al. Dis Colon Rectum. 2018; 61:284-92.

Each year, more than 2.2 million patients in the United States undergo evaluations for symptoms of hemorrhoids, according to updated guidelines on the management of hemorrhoids issued by the American Society of Colon and Rectal Surgeons.

“As a result, it is important to identify symptomatic hemorrhoids as the underlying source of the anorectal symptom and to have a clear understanding of the evaluation and management of this disease process,” wrote Bradley R. Davis, MD, FACS, chief of colon and rectal surgery at the Carolinas Medical Center, Charlotte, N.C., and the fellow members of the Clinical Practice Guidelines Committee of the ASCRS.

Dmitrii Kotin/Thinkstock.com

acssurgerynews@frontlinemedcom.com

SOURCE: Davis BR et al. Dis Colon Rectum. 2018; 61:284-92.

Each year, more than 2.2 million patients in the United States undergo evaluations for symptoms of hemorrhoids, according to updated guidelines on the management of hemorrhoids issued by the American Society of Colon and Rectal Surgeons.

“As a result, it is important to identify symptomatic hemorrhoids as the underlying source of the anorectal symptom and to have a clear understanding of the evaluation and management of this disease process,” wrote Bradley R. Davis, MD, FACS, chief of colon and rectal surgery at the Carolinas Medical Center, Charlotte, N.C., and the fellow members of the Clinical Practice Guidelines Committee of the ASCRS.

Dmitrii Kotin/Thinkstock.com

acssurgerynews@frontlinemedcom.com

SOURCE: Davis BR et al. Dis Colon Rectum. 2018; 61:284-92.

SAN DIEGO – In assessing tumor-free margins during Mohs micrographic surgery for skin cancer, bioimpedance spectroscopy was highly sensitive and specific for detecting residual cancer cells, compared with standard microscopy of histologic sections, in a single-center, pilot study of bioimpedance in 151 specimens from 50 consecutive patients.

If the finding of high diagnostic accuracy using bioimpedance spectroscopy is confirmed in larger numbers of patients and specimens run at multiple sites, this approach could “potentially revolutionize what happens with the way Mohs sections are processed in the future” by potentially shaving many minutes off the duration of a standard procedure, Darrell S. Rigel, MD, said in a video interview during the annual meeting of the American Academy of Dermatology.

Usually, it takes 10-20 minutes to process and examine Mohs specimens at each stage of the surgical procedure to determine whether additional excision must remove residual cancer cells, said Dr. Rigel, a dermatologist at New York University. In contrast, assessment for residual cancer cells in the surgical field takes less than a minute using bioimpedance spectroscopy, which relies on differences in electrical conductivity between benign and cancerous cells to identify cancer cells remaining at the surgical margins.

The results of the study were presented in a poster at the meeting, by a research associate of Dr. Rigel’s, Ryan Svoboda, MD, of the National Society for Cutaneous Medicine, New York.

The researchers used a bioimpedance spectroscopy device made by NovaScan to assess 151 histology slides prepared during Mohs micrographic surgery on patients with nonmelanoma skin cancer, and compared the findings against the gold standard of histological slide examination. By this criterion, bioimpedance spectroscopy identified 105 true negatives and 2 false negatives, and 43 true positives and 1 false positive. Calculations showed that this equated to 95.6% sensitivity, 99.1% specificity, a 97.7% positive predictive value, and a 98.1% negative predictive value.

These may be underestimates of the accuracy of bioimpedance spectroscopy because the calculations presume that conventional histology is always correct, but Dr. Rigel noted that sometimes the histological diagnosis is wrong.

mzoler@frontlinemedcom.com

SOURCE: Svoboda R et al. Poster 7304.

SAN DIEGO – In assessing tumor-free margins during Mohs micrographic surgery for skin cancer, bioimpedance spectroscopy was highly sensitive and specific for detecting residual cancer cells, compared with standard microscopy of histologic sections, in a single-center, pilot study of bioimpedance in 151 specimens from 50 consecutive patients.

If the finding of high diagnostic accuracy using bioimpedance spectroscopy is confirmed in larger numbers of patients and specimens run at multiple sites, this approach could “potentially revolutionize what happens with the way Mohs sections are processed in the future” by potentially shaving many minutes off the duration of a standard procedure, Darrell S. Rigel, MD, said in a video interview during the annual meeting of the American Academy of Dermatology.

Usually, it takes 10-20 minutes to process and examine Mohs specimens at each stage of the surgical procedure to determine whether additional excision must remove residual cancer cells, said Dr. Rigel, a dermatologist at New York University. In contrast, assessment for residual cancer cells in the surgical field takes less than a minute using bioimpedance spectroscopy, which relies on differences in electrical conductivity between benign and cancerous cells to identify cancer cells remaining at the surgical margins.

The results of the study were presented in a poster at the meeting, by a research associate of Dr. Rigel’s, Ryan Svoboda, MD, of the National Society for Cutaneous Medicine, New York.

The researchers used a bioimpedance spectroscopy device made by NovaScan to assess 151 histology slides prepared during Mohs micrographic surgery on patients with nonmelanoma skin cancer, and compared the findings against the gold standard of histological slide examination. By this criterion, bioimpedance spectroscopy identified 105 true negatives and 2 false negatives, and 43 true positives and 1 false positive. Calculations showed that this equated to 95.6% sensitivity, 99.1% specificity, a 97.7% positive predictive value, and a 98.1% negative predictive value.

These may be underestimates of the accuracy of bioimpedance spectroscopy because the calculations presume that conventional histology is always correct, but Dr. Rigel noted that sometimes the histological diagnosis is wrong.

mzoler@frontlinemedcom.com

SOURCE: Svoboda R et al. Poster 7304.

SAN DIEGO – In assessing tumor-free margins during Mohs micrographic surgery for skin cancer, bioimpedance spectroscopy was highly sensitive and specific for detecting residual cancer cells, compared with standard microscopy of histologic sections, in a single-center, pilot study of bioimpedance in 151 specimens from 50 consecutive patients.

If the finding of high diagnostic accuracy using bioimpedance spectroscopy is confirmed in larger numbers of patients and specimens run at multiple sites, this approach could “potentially revolutionize what happens with the way Mohs sections are processed in the future” by potentially shaving many minutes off the duration of a standard procedure, Darrell S. Rigel, MD, said in a video interview during the annual meeting of the American Academy of Dermatology.

Usually, it takes 10-20 minutes to process and examine Mohs specimens at each stage of the surgical procedure to determine whether additional excision must remove residual cancer cells, said Dr. Rigel, a dermatologist at New York University. In contrast, assessment for residual cancer cells in the surgical field takes less than a minute using bioimpedance spectroscopy, which relies on differences in electrical conductivity between benign and cancerous cells to identify cancer cells remaining at the surgical margins.

The results of the study were presented in a poster at the meeting, by a research associate of Dr. Rigel’s, Ryan Svoboda, MD, of the National Society for Cutaneous Medicine, New York.

The researchers used a bioimpedance spectroscopy device made by NovaScan to assess 151 histology slides prepared during Mohs micrographic surgery on patients with nonmelanoma skin cancer, and compared the findings against the gold standard of histological slide examination. By this criterion, bioimpedance spectroscopy identified 105 true negatives and 2 false negatives, and 43 true positives and 1 false positive. Calculations showed that this equated to 95.6% sensitivity, 99.1% specificity, a 97.7% positive predictive value, and a 98.1% negative predictive value.

These may be underestimates of the accuracy of bioimpedance spectroscopy because the calculations presume that conventional histology is always correct, but Dr. Rigel noted that sometimes the histological diagnosis is wrong.

mzoler@frontlinemedcom.com

SOURCE: Svoboda R et al. Poster 7304.

SAN DIEGO – An anti–interleukin-33 antibody aimed at atopic dermatitis performed reasonably well in a small, proof-of-concept phase 2a study, and will proceed along its developmental pathway.

All 12 patients who received one intravenous infusion of ANB020 achieved at least a 50% reduction in their Eczema Area and Severity Index (EASI) by day 29, Graham Ogg, MD, said at the annual meeting of the American Academy of Dermatology. Most of the improvement occurred in the first 2 weeks, was largely sustained for 2 months, then gradually began to fade, said Dr. Ogg, professor of dermatology at Oxford University, England.

The EASI improvement, along with improvements in itch and clinical assessment, are enough to propel ANB020 into a phase 2b, placebo-controlled, randomized trial, which Dr. Ogg said would recruit 200 to 300 adults with moderate to severe atomic dermatitis (AD).

ANB020 is a selective inhibitor of interleukin-33 (IL-33), which is highly expressed in the lesions of AD, Dr. Ogg said. “IL-33 is produced by a number of cells, including keratinocytes and epithelial cells. It’s an alarm molecule predominately produced after damage to keratinocytes; for example, after an allergenic challenge to the skin.”

The antibody has already passed its phase 1 trials, which included both a fixed and ascending dose study of 10 mg to 750 mg in healthy adults. ANB020 has a long half-life of 16 days after IV infusion or subcutaneous injection, inhibits IL-33 for up to 85 days, and has no apparent dose-limiting toxicities.

The phase 2a study comprised 12 adults (mean age 40 years) with a mean EASI score of 32, Dr. Ogg reported. The mean Investigator’s Global Assessment score was 4, and the mean Severity Scoring of Atopic Dermatitis almost 65. Patients had high itch scores and scored a mean of 13 on the Dermatology Life Quality Index. All were inadequately controlled on topical corticosteroids, and about half had failed at least one systemic immunomodulator.

Following a washout period, all subjects received an initial placebo infusion, and 1 week later received a single 300-mg infusion of ANB020. The primary endpoint – at least a 50% reduction in EASI score (EASI-50) – was assessed at day 29, with close follow-up until day 140.

By day 15, nine patients (75%) had achieved EASI-50, and three (25%) had achieved a 75% reduction in EASI score (EASI-75). The average EASI score reduction was 58% at that point. By day 29, 10 (83%) had achieved EASI-50, and 4 (33%), EASI-75. This benefit was largely maintained until day 78, when it began to tail off somewhat. By day 140, five patients (42%) still had an EASI-50 and three (25%), an EASI-75.

Three patients (25%) achieved an Investigator’s Global Assessment score of 0 or 1, indicating clear or almost clear skin. On day 29, the average pruritus decrease was 32%, which dropped to 21% by day 140. The average Severity Scoring of Atopic Dermatitis reduction was 40% on day 29 and 32% on day 140. The average Dermatology Life Quality Index reduction was 45% on day 29 and 43% on day 140.

ANB020 was well tolerated with no drug-related safety signals. Dizziness occurred in 17% of subjects, and mild headache in 25%. There was one serious adverse event, a case of major depression that occurred on day 140. This was consistent with the patient’s baseline health history and deemed unrelated to the study drug.

According to an AnaptysBio press release, ANB020 is also being investigated in a double-blind, placebo-controlled study of 20 adults with severe peanut allergy. The company also is enrolling a 24-patient randomized, double-blind, placebo-controlled, phase 2a trial in adults with severe eosinophilic asthma.

Topline data from both of these studies are expected soon, the website noted.

AnaptysBio funded Dr. Ogg’s travel and registration fees for the meeting. He said he had no other financial disclosures relevant to ANB020.

msullivan@frontlinemedcom.com

SOURCE: Ogg G et al. AAD 2018. Abstract 6658.

SAN DIEGO – An anti–interleukin-33 antibody aimed at atopic dermatitis performed reasonably well in a small, proof-of-concept phase 2a study, and will proceed along its developmental pathway.

All 12 patients who received one intravenous infusion of ANB020 achieved at least a 50% reduction in their Eczema Area and Severity Index (EASI) by day 29, Graham Ogg, MD, said at the annual meeting of the American Academy of Dermatology. Most of the improvement occurred in the first 2 weeks, was largely sustained for 2 months, then gradually began to fade, said Dr. Ogg, professor of dermatology at Oxford University, England.

The EASI improvement, along with improvements in itch and clinical assessment, are enough to propel ANB020 into a phase 2b, placebo-controlled, randomized trial, which Dr. Ogg said would recruit 200 to 300 adults with moderate to severe atomic dermatitis (AD).

ANB020 is a selective inhibitor of interleukin-33 (IL-33), which is highly expressed in the lesions of AD, Dr. Ogg said. “IL-33 is produced by a number of cells, including keratinocytes and epithelial cells. It’s an alarm molecule predominately produced after damage to keratinocytes; for example, after an allergenic challenge to the skin.”

The antibody has already passed its phase 1 trials, which included both a fixed and ascending dose study of 10 mg to 750 mg in healthy adults. ANB020 has a long half-life of 16 days after IV infusion or subcutaneous injection, inhibits IL-33 for up to 85 days, and has no apparent dose-limiting toxicities.

The phase 2a study comprised 12 adults (mean age 40 years) with a mean EASI score of 32, Dr. Ogg reported. The mean Investigator’s Global Assessment score was 4, and the mean Severity Scoring of Atopic Dermatitis almost 65. Patients had high itch scores and scored a mean of 13 on the Dermatology Life Quality Index. All were inadequately controlled on topical corticosteroids, and about half had failed at least one systemic immunomodulator.

Following a washout period, all subjects received an initial placebo infusion, and 1 week later received a single 300-mg infusion of ANB020. The primary endpoint – at least a 50% reduction in EASI score (EASI-50) – was assessed at day 29, with close follow-up until day 140.

By day 15, nine patients (75%) had achieved EASI-50, and three (25%) had achieved a 75% reduction in EASI score (EASI-75). The average EASI score reduction was 58% at that point. By day 29, 10 (83%) had achieved EASI-50, and 4 (33%), EASI-75. This benefit was largely maintained until day 78, when it began to tail off somewhat. By day 140, five patients (42%) still had an EASI-50 and three (25%), an EASI-75.

Three patients (25%) achieved an Investigator’s Global Assessment score of 0 or 1, indicating clear or almost clear skin. On day 29, the average pruritus decrease was 32%, which dropped to 21% by day 140. The average Severity Scoring of Atopic Dermatitis reduction was 40% on day 29 and 32% on day 140. The average Dermatology Life Quality Index reduction was 45% on day 29 and 43% on day 140.

ANB020 was well tolerated with no drug-related safety signals. Dizziness occurred in 17% of subjects, and mild headache in 25%. There was one serious adverse event, a case of major depression that occurred on day 140. This was consistent with the patient’s baseline health history and deemed unrelated to the study drug.

According to an AnaptysBio press release, ANB020 is also being investigated in a double-blind, placebo-controlled study of 20 adults with severe peanut allergy. The company also is enrolling a 24-patient randomized, double-blind, placebo-controlled, phase 2a trial in adults with severe eosinophilic asthma.

Topline data from both of these studies are expected soon, the website noted.

AnaptysBio funded Dr. Ogg’s travel and registration fees for the meeting. He said he had no other financial disclosures relevant to ANB020.

msullivan@frontlinemedcom.com

SOURCE: Ogg G et al. AAD 2018. Abstract 6658.

SAN DIEGO – An anti–interleukin-33 antibody aimed at atopic dermatitis performed reasonably well in a small, proof-of-concept phase 2a study, and will proceed along its developmental pathway.

All 12 patients who received one intravenous infusion of ANB020 achieved at least a 50% reduction in their Eczema Area and Severity Index (EASI) by day 29, Graham Ogg, MD, said at the annual meeting of the American Academy of Dermatology. Most of the improvement occurred in the first 2 weeks, was largely sustained for 2 months, then gradually began to fade, said Dr. Ogg, professor of dermatology at Oxford University, England.

The EASI improvement, along with improvements in itch and clinical assessment, are enough to propel ANB020 into a phase 2b, placebo-controlled, randomized trial, which Dr. Ogg said would recruit 200 to 300 adults with moderate to severe atomic dermatitis (AD).

ANB020 is a selective inhibitor of interleukin-33 (IL-33), which is highly expressed in the lesions of AD, Dr. Ogg said. “IL-33 is produced by a number of cells, including keratinocytes and epithelial cells. It’s an alarm molecule predominately produced after damage to keratinocytes; for example, after an allergenic challenge to the skin.”

The antibody has already passed its phase 1 trials, which included both a fixed and ascending dose study of 10 mg to 750 mg in healthy adults. ANB020 has a long half-life of 16 days after IV infusion or subcutaneous injection, inhibits IL-33 for up to 85 days, and has no apparent dose-limiting toxicities.

The phase 2a study comprised 12 adults (mean age 40 years) with a mean EASI score of 32, Dr. Ogg reported. The mean Investigator’s Global Assessment score was 4, and the mean Severity Scoring of Atopic Dermatitis almost 65. Patients had high itch scores and scored a mean of 13 on the Dermatology Life Quality Index. All were inadequately controlled on topical corticosteroids, and about half had failed at least one systemic immunomodulator.

Following a washout period, all subjects received an initial placebo infusion, and 1 week later received a single 300-mg infusion of ANB020. The primary endpoint – at least a 50% reduction in EASI score (EASI-50) – was assessed at day 29, with close follow-up until day 140.

By day 15, nine patients (75%) had achieved EASI-50, and three (25%) had achieved a 75% reduction in EASI score (EASI-75). The average EASI score reduction was 58% at that point. By day 29, 10 (83%) had achieved EASI-50, and 4 (33%), EASI-75. This benefit was largely maintained until day 78, when it began to tail off somewhat. By day 140, five patients (42%) still had an EASI-50 and three (25%), an EASI-75.

Three patients (25%) achieved an Investigator’s Global Assessment score of 0 or 1, indicating clear or almost clear skin. On day 29, the average pruritus decrease was 32%, which dropped to 21% by day 140. The average Severity Scoring of Atopic Dermatitis reduction was 40% on day 29 and 32% on day 140. The average Dermatology Life Quality Index reduction was 45% on day 29 and 43% on day 140.

ANB020 was well tolerated with no drug-related safety signals. Dizziness occurred in 17% of subjects, and mild headache in 25%. There was one serious adverse event, a case of major depression that occurred on day 140. This was consistent with the patient’s baseline health history and deemed unrelated to the study drug.

According to an AnaptysBio press release, ANB020 is also being investigated in a double-blind, placebo-controlled study of 20 adults with severe peanut allergy. The company also is enrolling a 24-patient randomized, double-blind, placebo-controlled, phase 2a trial in adults with severe eosinophilic asthma.

Topline data from both of these studies are expected soon, the website noted.

AnaptysBio funded Dr. Ogg’s travel and registration fees for the meeting. He said he had no other financial disclosures relevant to ANB020.

msullivan@frontlinemedcom.com

SOURCE: Ogg G et al. AAD 2018. Abstract 6658.

Open surgery for inflammatory bowel disease (IBD) has been known to carry a high risk of incisional hernia, but the risk factors have not been well understood.

A review of 1,000 operations performed over nearly 40 years at a high-volume, nationally recognized center has identified five patient factors that can raise the risk of incisional hernia in these operations by 50% or more, according to a study published in the Annals of Surgery.

VILevi/Thinkstock

The study followed the patients for an average of 8 years after their operations, which were performed between January 1976 and December 2014 at Mount Sinai Medical Center in New York. The overall incidence of incisional hernia was 20%-21% for patients with ulcerative colitis and 20% for those with Crohn’s disease.

SOURCE: Heimann T et al. Ann Surg. 2018 Mar;267(3):532-6.

Open surgery for inflammatory bowel disease (IBD) has been known to carry a high risk of incisional hernia, but the risk factors have not been well understood.

A review of 1,000 operations performed over nearly 40 years at a high-volume, nationally recognized center has identified five patient factors that can raise the risk of incisional hernia in these operations by 50% or more, according to a study published in the Annals of Surgery.

VILevi/Thinkstock

The study followed the patients for an average of 8 years after their operations, which were performed between January 1976 and December 2014 at Mount Sinai Medical Center in New York. The overall incidence of incisional hernia was 20%-21% for patients with ulcerative colitis and 20% for those with Crohn’s disease.

SOURCE: Heimann T et al. Ann Surg. 2018 Mar;267(3):532-6.

Open surgery for inflammatory bowel disease (IBD) has been known to carry a high risk of incisional hernia, but the risk factors have not been well understood.

A review of 1,000 operations performed over nearly 40 years at a high-volume, nationally recognized center has identified five patient factors that can raise the risk of incisional hernia in these operations by 50% or more, according to a study published in the Annals of Surgery.

VILevi/Thinkstock

The study followed the patients for an average of 8 years after their operations, which were performed between January 1976 and December 2014 at Mount Sinai Medical Center in New York. The overall incidence of incisional hernia was 20%-21% for patients with ulcerative colitis and 20% for those with Crohn’s disease.

SOURCE: Heimann T et al. Ann Surg. 2018 Mar;267(3):532-6.

Adding social recovery therapy to early intervention services significantly improved social function, compared with early intervention alone for young first-episode psychosis patients with extreme social withdrawal, according to data from 155 patients.

“New interventions targeting functional and social recovery are needed in people with first-episode psychosis,” wrote David Fowler of the psychology department at the University of Sussex, Brighton, England, and his colleagues.

In a study known as SUPEREDEN3, published in The Lancet Psychiatry, the researchers randomized 76 patients aged 16-35 years to social recovery therapy plus early intervention and 79 to early intervention alone. The study participants were selected between Oct. 1, 2012, and June 20, 2014, and suffered from extreme social withdrawal as well as complex comorbidities, including anxiety and depression, hopelessness, and residual and treatment-resistant positive psychotic symptoms.

The social recovery therapy, delivered in three stages, included working with the patients to identify new activities and to get them engaged in those pursuits. “Therapists adopt an assertive outreach style of contact, most frequently visiting people at home or in community settings,” the researchers wrote. “Therapists are also encouraged to work systematically with family members, employers, and educational providers to discuss and overcome potential problems that could impede social recovery.”

After 9 months, the social recovery group averaged 8 more hours of structured activity compared with the control group in an intent-to-treat analysis. Structured activity was defined as time spent over the previous month on activities, including work, education, volunteering, leisure activities, sports, housework or other chores, and child care. No adverse events related to the intervention were reported.

“Our findings show that social recovery therapy plus early intervention services is superior to early intervention services alone on the primary outcome of time spent in structured activity,” Mr. Fowler and his colleagues wrote.

The findings were limited by the lack of data from secondary outcomes, in part because of the challenges of following up with a withdrawn study population, the researchers said. However, they said, the study is the first to show benefits of social recovery therapy in this challenging group.

The results offer “encouragement for practitioners in early intervention services to focus on this subgroup who are often neglected. Our results also suggest that social recovery therapy techniques could be a useful addition in this group,” the researchers said.

The National Institute for Health Research funded the study. The researchers had no financial conflicts to disclose.

SOURCE: Fowler D et al. Lancet Psychiatry. 2018 Jan;5(1):41-50.

Adding social recovery therapy to early intervention services significantly improved social function, compared with early intervention alone for young first-episode psychosis patients with extreme social withdrawal, according to data from 155 patients.

“New interventions targeting functional and social recovery are needed in people with first-episode psychosis,” wrote David Fowler of the psychology department at the University of Sussex, Brighton, England, and his colleagues.

In a study known as SUPEREDEN3, published in The Lancet Psychiatry, the researchers randomized 76 patients aged 16-35 years to social recovery therapy plus early intervention and 79 to early intervention alone. The study participants were selected between Oct. 1, 2012, and June 20, 2014, and suffered from extreme social withdrawal as well as complex comorbidities, including anxiety and depression, hopelessness, and residual and treatment-resistant positive psychotic symptoms.

The social recovery therapy, delivered in three stages, included working with the patients to identify new activities and to get them engaged in those pursuits. “Therapists adopt an assertive outreach style of contact, most frequently visiting people at home or in community settings,” the researchers wrote. “Therapists are also encouraged to work systematically with family members, employers, and educational providers to discuss and overcome potential problems that could impede social recovery.”

After 9 months, the social recovery group averaged 8 more hours of structured activity compared with the control group in an intent-to-treat analysis. Structured activity was defined as time spent over the previous month on activities, including work, education, volunteering, leisure activities, sports, housework or other chores, and child care. No adverse events related to the intervention were reported.

“Our findings show that social recovery therapy plus early intervention services is superior to early intervention services alone on the primary outcome of time spent in structured activity,” Mr. Fowler and his colleagues wrote.

The findings were limited by the lack of data from secondary outcomes, in part because of the challenges of following up with a withdrawn study population, the researchers said. However, they said, the study is the first to show benefits of social recovery therapy in this challenging group.

The results offer “encouragement for practitioners in early intervention services to focus on this subgroup who are often neglected. Our results also suggest that social recovery therapy techniques could be a useful addition in this group,” the researchers said.

The National Institute for Health Research funded the study. The researchers had no financial conflicts to disclose.

SOURCE: Fowler D et al. Lancet Psychiatry. 2018 Jan;5(1):41-50.

Adding social recovery therapy to early intervention services significantly improved social function, compared with early intervention alone for young first-episode psychosis patients with extreme social withdrawal, according to data from 155 patients.

“New interventions targeting functional and social recovery are needed in people with first-episode psychosis,” wrote David Fowler of the psychology department at the University of Sussex, Brighton, England, and his colleagues.

In a study known as SUPEREDEN3, published in The Lancet Psychiatry, the researchers randomized 76 patients aged 16-35 years to social recovery therapy plus early intervention and 79 to early intervention alone. The study participants were selected between Oct. 1, 2012, and June 20, 2014, and suffered from extreme social withdrawal as well as complex comorbidities, including anxiety and depression, hopelessness, and residual and treatment-resistant positive psychotic symptoms.

The social recovery therapy, delivered in three stages, included working with the patients to identify new activities and to get them engaged in those pursuits. “Therapists adopt an assertive outreach style of contact, most frequently visiting people at home or in community settings,” the researchers wrote. “Therapists are also encouraged to work systematically with family members, employers, and educational providers to discuss and overcome potential problems that could impede social recovery.”

After 9 months, the social recovery group averaged 8 more hours of structured activity compared with the control group in an intent-to-treat analysis. Structured activity was defined as time spent over the previous month on activities, including work, education, volunteering, leisure activities, sports, housework or other chores, and child care. No adverse events related to the intervention were reported.

“Our findings show that social recovery therapy plus early intervention services is superior to early intervention services alone on the primary outcome of time spent in structured activity,” Mr. Fowler and his colleagues wrote.

The findings were limited by the lack of data from secondary outcomes, in part because of the challenges of following up with a withdrawn study population, the researchers said. However, they said, the study is the first to show benefits of social recovery therapy in this challenging group.

The results offer “encouragement for practitioners in early intervention services to focus on this subgroup who are often neglected. Our results also suggest that social recovery therapy techniques could be a useful addition in this group,” the researchers said.

The National Institute for Health Research funded the study. The researchers had no financial conflicts to disclose.

SOURCE: Fowler D et al. Lancet Psychiatry. 2018 Jan;5(1):41-50.

Preoperative weight loss improves bariatric surgery outcomes, according to findings from a single-institution retrospective analysis. The weight loss came from following a 4-week low-calorie diet (LCD) and was of greatest benefit to patients who lost 8% or more of their excess weight. These patients had a greater loss of excess weight in the 12 months following surgery, as well as shorter average hospital length of stay.

The results appeared online in the Journal of the American College of Surgeons.

Preliminary studies indicated that short-term weight loss before surgery might reduce surgical complexity by reducing the size of the liver and intra-abdominal fat mass, but it remained uncertain what effect weight loss might have on long-term outcomes.

The AGA Obesity Practice Guide was created to provide a comprehensive, multidisciplinary process to personalize innovative obesity care for safe and effective weight management, including nonsurgical and endoscopic management of obesity. Learn more at www.gastro.org/obesity.

SOURCE: Hutcheon DA et al. J Am Coll Surgeons. 2018 Jan 31. doi: 10.1016/j.jamcollsurg.2017.12.032.

Preoperative weight loss improves bariatric surgery outcomes, according to findings from a single-institution retrospective analysis. The weight loss came from following a 4-week low-calorie diet (LCD) and was of greatest benefit to patients who lost 8% or more of their excess weight. These patients had a greater loss of excess weight in the 12 months following surgery, as well as shorter average hospital length of stay.

The results appeared online in the Journal of the American College of Surgeons.

Preliminary studies indicated that short-term weight loss before surgery might reduce surgical complexity by reducing the size of the liver and intra-abdominal fat mass, but it remained uncertain what effect weight loss might have on long-term outcomes.

The AGA Obesity Practice Guide was created to provide a comprehensive, multidisciplinary process to personalize innovative obesity care for safe and effective weight management, including nonsurgical and endoscopic management of obesity. Learn more at www.gastro.org/obesity.

SOURCE: Hutcheon DA et al. J Am Coll Surgeons. 2018 Jan 31. doi: 10.1016/j.jamcollsurg.2017.12.032.

Preoperative weight loss improves bariatric surgery outcomes, according to findings from a single-institution retrospective analysis. The weight loss came from following a 4-week low-calorie diet (LCD) and was of greatest benefit to patients who lost 8% or more of their excess weight. These patients had a greater loss of excess weight in the 12 months following surgery, as well as shorter average hospital length of stay.

The results appeared online in the Journal of the American College of Surgeons.

Preliminary studies indicated that short-term weight loss before surgery might reduce surgical complexity by reducing the size of the liver and intra-abdominal fat mass, but it remained uncertain what effect weight loss might have on long-term outcomes.

The AGA Obesity Practice Guide was created to provide a comprehensive, multidisciplinary process to personalize innovative obesity care for safe and effective weight management, including nonsurgical and endoscopic management of obesity. Learn more at www.gastro.org/obesity.

SOURCE: Hutcheon DA et al. J Am Coll Surgeons. 2018 Jan 31. doi: 10.1016/j.jamcollsurg.2017.12.032.

Background: The association between platelet counts, risk of bleeding, and transfusions in patients with thrombocytopenia related to stem cell transplant (SCT) or chemotherapy is not clear, except at very low platelet counts.

Study design: Secondary analysis of a multicenter, randomized controlled trial, stratified by cause of thrombocytopenia: autologous or syngeneic SCT (AUTO), allogeneic SCT (ALLO), or chemotherapy for hematologic malignancy without SCT (CHEMO).

Setting: Twenty-six hospitals from 2004 to 2007.

Synopsis: The PLADO trial enrolled more than 1,200 patients aged 18 years and older expected to experience a period of hypoproliferative thrombocytopenia as a result of chemotherapy or SCT, and randomized them to low, medium, or high doses of prophylactic platelets. This secondary analysis assessed laboratory predictors of bleeding, and the effect of transfusion.

Of 1,077 patients who received platelet transfusions, there were no differences between dose groups for any bleeding outcomes. Over a wide range of platelet counts, the ALLO stratum had a higher risk of bleeding than other strata, with clinically significant bleeding on 21% of patient-days in the ALLO stratum, compared with 19% in the AUTO stratum and 11% in the CHEMO stratum (P less than .001). Risk for bleeding was significantly higher at platelet counts of equal to or less than 5x109/L compared with platelet counts greater than or equal to 81x109/L. Higher aPTT and INR were also associated with higher risk of clinically significant bleeding. In a multipredictor model, only hematocrit was significantly associated with more severe bleeding. Neither platelet transfusion nor RBC transfusion reduced the risk of bleeding on the following day, although the authors note some possibility of confounding by indication.

Bottom line: Predictors of overall increased risk for bleeding in patients with secondary hypoproliferative thrombocytopenia were treatment stratum, platelet counts less than or equal to 5x109/L, hematocrit less than 25%, INR greater than 1.2, and aPTT greater than 30 seconds. This study challenges the conventional wisdom that transfusions reduce bleeding risk in patients with secondary hypoproliferative thrombocytopenia.

Citation: Uhl L, Assmann SF, Hamza TH, et al. Laboratory predictors of bleeding and the effect of platelet and RBC transfusions on bleeding outcomes in the PLADO trial. Blood. 2017;130(10):1247-58.

Background: The association between platelet counts, risk of bleeding, and transfusions in patients with thrombocytopenia related to stem cell transplant (SCT) or chemotherapy is not clear, except at very low platelet counts.

Study design: Secondary analysis of a multicenter, randomized controlled trial, stratified by cause of thrombocytopenia: autologous or syngeneic SCT (AUTO), allogeneic SCT (ALLO), or chemotherapy for hematologic malignancy without SCT (CHEMO).

Setting: Twenty-six hospitals from 2004 to 2007.

Synopsis: The PLADO trial enrolled more than 1,200 patients aged 18 years and older expected to experience a period of hypoproliferative thrombocytopenia as a result of chemotherapy or SCT, and randomized them to low, medium, or high doses of prophylactic platelets. This secondary analysis assessed laboratory predictors of bleeding, and the effect of transfusion.

Of 1,077 patients who received platelet transfusions, there were no differences between dose groups for any bleeding outcomes. Over a wide range of platelet counts, the ALLO stratum had a higher risk of bleeding than other strata, with clinically significant bleeding on 21% of patient-days in the ALLO stratum, compared with 19% in the AUTO stratum and 11% in the CHEMO stratum (P less than .001). Risk for bleeding was significantly higher at platelet counts of equal to or less than 5x109/L compared with platelet counts greater than or equal to 81x109/L. Higher aPTT and INR were also associated with higher risk of clinically significant bleeding. In a multipredictor model, only hematocrit was significantly associated with more severe bleeding. Neither platelet transfusion nor RBC transfusion reduced the risk of bleeding on the following day, although the authors note some possibility of confounding by indication.

Bottom line: Predictors of overall increased risk for bleeding in patients with secondary hypoproliferative thrombocytopenia were treatment stratum, platelet counts less than or equal to 5x109/L, hematocrit less than 25%, INR greater than 1.2, and aPTT greater than 30 seconds. This study challenges the conventional wisdom that transfusions reduce bleeding risk in patients with secondary hypoproliferative thrombocytopenia.

Citation: Uhl L, Assmann SF, Hamza TH, et al. Laboratory predictors of bleeding and the effect of platelet and RBC transfusions on bleeding outcomes in the PLADO trial. Blood. 2017;130(10):1247-58.

Background: The association between platelet counts, risk of bleeding, and transfusions in patients with thrombocytopenia related to stem cell transplant (SCT) or chemotherapy is not clear, except at very low platelet counts.

Study design: Secondary analysis of a multicenter, randomized controlled trial, stratified by cause of thrombocytopenia: autologous or syngeneic SCT (AUTO), allogeneic SCT (ALLO), or chemotherapy for hematologic malignancy without SCT (CHEMO).

Setting: Twenty-six hospitals from 2004 to 2007.

Synopsis: The PLADO trial enrolled more than 1,200 patients aged 18 years and older expected to experience a period of hypoproliferative thrombocytopenia as a result of chemotherapy or SCT, and randomized them to low, medium, or high doses of prophylactic platelets. This secondary analysis assessed laboratory predictors of bleeding, and the effect of transfusion.

Of 1,077 patients who received platelet transfusions, there were no differences between dose groups for any bleeding outcomes. Over a wide range of platelet counts, the ALLO stratum had a higher risk of bleeding than other strata, with clinically significant bleeding on 21% of patient-days in the ALLO stratum, compared with 19% in the AUTO stratum and 11% in the CHEMO stratum (P less than .001). Risk for bleeding was significantly higher at platelet counts of equal to or less than 5x109/L compared with platelet counts greater than or equal to 81x109/L. Higher aPTT and INR were also associated with higher risk of clinically significant bleeding. In a multipredictor model, only hematocrit was significantly associated with more severe bleeding. Neither platelet transfusion nor RBC transfusion reduced the risk of bleeding on the following day, although the authors note some possibility of confounding by indication.

Bottom line: Predictors of overall increased risk for bleeding in patients with secondary hypoproliferative thrombocytopenia were treatment stratum, platelet counts less than or equal to 5x109/L, hematocrit less than 25%, INR greater than 1.2, and aPTT greater than 30 seconds. This study challenges the conventional wisdom that transfusions reduce bleeding risk in patients with secondary hypoproliferative thrombocytopenia.

Citation: Uhl L, Assmann SF, Hamza TH, et al. Laboratory predictors of bleeding and the effect of platelet and RBC transfusions on bleeding outcomes in the PLADO trial. Blood. 2017;130(10):1247-58.

In 2003, the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Maternal-Fetal Medicine Units (MFMU) Network reported on a placebo-controlled randomized study of 17–alpha hydroxyprogesterone caproate (17-OHPC) in women with a history of spontaneous preterm delivery. The study demonstrated a 33% reduction in recurrent preterm birth after weekly treatment with 17-OHPC, which was initiated at 16-20 weeks of gestation.

This landmark study, led by Paul Meis, MD, validated what had been suggested in an earlier meta-analysis (1990) by Mark Keirse, MD – and it quickly altered clinical practice. It set into motion a string of studies on the use of 17-OHPC and other progestational compounds in women with a variety of conditions associated with an increased risk for preterm birth.

Consensus

One area in which there is agreement concerns the use of 17-OHPC intramuscular injections in multifetal gestations. Two randomized clinical trials undertaken by the MFMU Network – one in twins and one in triplets – concluded that 17-OHPC is ineffective in reducing the rate of preterm birth. Moreover, in another, more recent MFMU Network study, there was a negative linear relationship between concentrations of 17-OHPC and gestational age at delivery. Women with twin gestations who had higher concentrations of 17-OHPC delivered at earlier gestational ages than women with lower concentrations (Am J Obstet Gynecol. 2012;207[5]:396.e1-8).

Other investigators have similarly shown in clinical trials that the preterm birth rate actually seems to be worsened in multifetal gestations when 17-OHPC is used. There is now widespread agreement that the compound should not be used in these patients.

In addition, an MFMU Network study led by William A. Grobman, MD, demonstrated that 17-OHPC (250-mg injections) does not provide any benefit to nulliparous women with a sonographic cervical length less than 30 mm (Am J Obstet Gynecol. 2012;207[5]:390.e1-8). Other studies utilizing higher doses of 17-OHPC similarly found no benefit. There is also agreement that 17-OHPC has no benefit in treating women with preterm premature rupture of the membranes, preterm labor, or as a maintenance treatment after an episode of preterm labor.

General agreement without consensus

There is general agreement that women with a singleton gestation and a prior spontaneous preterm birth should be offered 17-OHPC, and that women with a singleton gestation and a midtrimester shortened cervical length should be offered vaginal progesterone and not 17-OHPC. However, even in these populations, there are questions about efficacy, dosing, and other issues.

In the Meis study (N Engl J Med. 2003;348:2379-85), treatment with 17-OHPC in women with a singleton gestation and a prior preterm delivery significantly reduced the risk of another preterm birth at less than 37 weeks’ gestation (36.3% in the progesterone group vs. 54.9% in the placebo group; relative risk, 0.66), at less than 35 weeks’ gestation (RR, 0.67), and at less than 32 weeks’ gestation (RR, 0.58). The exceptionally high rate of preterm delivery in the placebo group, however, prompted other investigators to express concern in published correspondence that the study was potentially flawed.

We reported an inverse relationship between 17-OHPC concentration and spontaneous preterm birth as part of a study conducted with the MFMU Network and the Obstetrical-Fetal Pharmacology Research Units Network. All women in the study had singleton gestations and received 250 mg weekly 17-OHPC (the broader study was designed to evaluate the benefit of omega-3 supplementation). We measured plasma concentrations of 17-OHPC and found that women with concentrations in the lowest quartile had a significantly higher risk of preterm birth and delivered at significantly earlier gestational ages than did women in the second through fourth quartiles (Am J Obstet Gynecol. 2014;210[2]:128.e1-6).

Other studies/abstracts similarly evaluating the relationship between 17-OHPC concentrations and preterm birth have reported mixed results, with both validation and refutation of our findings.

Research underway may help settle the controversy. In an ongoing, open-label pharmacology study being conducted by the Obstetrical-Fetal Pharmacology Research Units Network, women with singleton pregnancies and a history of prior preterm birth are being randomly assigned to receive either 250 mg (the empirically chosen, currently recommended dose) or 500 mg 17-OHPC. A relationship between the plasma concentration of 17-OHPC at 26-30 weeks’ gestation and the incidence of preterm birth would offer proof of efficacy and could help elucidate the therapeutic dosing; if there is no relationship, we revert to the question of whether the agent really works. Based on current evidence, both the Society for Maternal-Fetal Medicine (SMFM) and the American College of Obstetricians and Gynecologists (ACOG) support the use of 17-OHPC for prevention of sPTB in women with a prior sPTB.

Questions about vaginal progesterone have also been somewhat unsettled. Eduardo B. Fonseca, MD, reported in 2007 that asymptomatic women with a short cervix (defined as 15 mm or less) who were randomized to receive vaginal progesterone at a median of 22 weeks’ gestation had a significantly lower rate of preterm birth before 34 weeks’ gestation than those who received placebo (RR, 0.56; N Engl J Med. 2007;357[5]:462-9). Research that followed offered mixed conclusions, with a study by Sonia S. Hassan, MD, showing benefit and a study by Jane E. Norman, MD, showing no benefit. Notably, in 2012, the Food and Drug Administration voted against approval of a sustained-release progesterone vaginal gel, citing research results that were not sufficiently compelling.

Still, vaginal progesterone has been endorsed by both ACOG and by the SMFM for women with a short cervical length in the midtrimester. This is supported by a new review and meta-analysis of individual patient data by Roberto Romero, MD, in which vaginal progesterone was found to significantly decrease the risk of preterm birth in singleton gestations with a midtrimester cervical length of 25 mm or less. The reduction occurred over a wide range of gestational ages, including at less than 33 weeks of gestation (RR, 0.62; Am J Obstet Gynecol. 2018 Feb;218[2]:161-80).
 

Disagreement

Some have argued that vaginal progesterone should be offered to women with a history of prior spontaneous preterm birth, but the largest study to look at this application – a randomized multinational trial reported by John M. O’Brien, MD, and his colleagues in 2007 – found that use of the compound did not reduce the frequency of recurrent preterm birth at or before 32 weeks. Others have argued that vaginal progesterone is of benefit in this group of women based on a combination of multiple subgroup analyses. There is disagreement between ACOG and SMFM on this issue. ACOG supports the use of vaginal progesterone for women with a prior preterm birth but the SMFM strongly rejects this treatment and only endorses 17-OHPC for this indication.

Unresolved

The value of vaginal progesterone supplementation in reducing preterm births in women with twin gestations is under continuing investigation, including a study of women with twin gestation and a short cervix. This MFMU Network randomized trial, now underway, is evaluating the effectiveness of vaginal progesterone or pessary, compared with placebo, in preventing early preterm birth in women carrying twins who have a cervical length less than 30 mm.

Another question about the use of progesterone concerns the woman who delivered preterm during a twin gestation and is now pregnant with a singleton gestation. Should anything be offered to her? This is a question that has not yet been addressed in the literature.

What does seem clear is that spontaneous preterm birth is a multifactorial condition with numerous causes, and quite possibly an interaction between genetics, maternal characteristics, and the environment surrounding each pregnancy (Semin Perinatol. 2016;40[5]:273-80). Certainly, there are different pathways and mechanisms at play in patients who deliver at 35-36 weeks, for instance, compared with those who deliver at 25-26 weeks.

We recently obtained cervical fluid from pregnant women with prior preterm births and analyzed the samples for concentrations of cytokines and matrix metalloproteinases. Women with a prior early preterm delivery at less than 26 weeks had elevations in five cervical cytokines – an inflammatory signature, in essence – while those whose prior preterm birth occurred at a later gestational age had no elevations of these cytokines (Am J Perinatol. 2017 Nov 15. doi: 10.1055/s-0037-1608631).

Hopefully, we soon will be able to identify subpopulations of pregnant women who will benefit more from progesterone supplementation. More research needs to be done at a granular level, with more narrowly defined populations – and with consideration of various pharmacologic, genetic and environmental factors – in order to develop a more specific treatment approach. In the meantime, it is important to appreciate the unknowns that underlie the highly variable clinical responses and outcomes seen in our clinical trials.

Dr. Caritis is professor of obstetrics, gynecology, and reproductive sciences at Magee-Womens Hospital, University of Pittsburgh. He has no disclosures relevant to this Master Class.

In 2003, the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Maternal-Fetal Medicine Units (MFMU) Network reported on a placebo-controlled randomized study of 17–alpha hydroxyprogesterone caproate (17-OHPC) in women with a history of spontaneous preterm delivery. The study demonstrated a 33% reduction in recurrent preterm birth after weekly treatment with 17-OHPC, which was initiated at 16-20 weeks of gestation.

This landmark study, led by Paul Meis, MD, validated what had been suggested in an earlier meta-analysis (1990) by Mark Keirse, MD – and it quickly altered clinical practice. It set into motion a string of studies on the use of 17-OHPC and other progestational compounds in women with a variety of conditions associated with an increased risk for preterm birth.

Consensus

One area in which there is agreement concerns the use of 17-OHPC intramuscular injections in multifetal gestations. Two randomized clinical trials undertaken by the MFMU Network – one in twins and one in triplets – concluded that 17-OHPC is ineffective in reducing the rate of preterm birth. Moreover, in another, more recent MFMU Network study, there was a negative linear relationship between concentrations of 17-OHPC and gestational age at delivery. Women with twin gestations who had higher concentrations of 17-OHPC delivered at earlier gestational ages than women with lower concentrations (Am J Obstet Gynecol. 2012;207[5]:396.e1-8).

Other investigators have similarly shown in clinical trials that the preterm birth rate actually seems to be worsened in multifetal gestations when 17-OHPC is used. There is now widespread agreement that the compound should not be used in these patients.

In addition, an MFMU Network study led by William A. Grobman, MD, demonstrated that 17-OHPC (250-mg injections) does not provide any benefit to nulliparous women with a sonographic cervical length less than 30 mm (Am J Obstet Gynecol. 2012;207[5]:390.e1-8). Other studies utilizing higher doses of 17-OHPC similarly found no benefit. There is also agreement that 17-OHPC has no benefit in treating women with preterm premature rupture of the membranes, preterm labor, or as a maintenance treatment after an episode of preterm labor.

General agreement without consensus

There is general agreement that women with a singleton gestation and a prior spontaneous preterm birth should be offered 17-OHPC, and that women with a singleton gestation and a midtrimester shortened cervical length should be offered vaginal progesterone and not 17-OHPC. However, even in these populations, there are questions about efficacy, dosing, and other issues.

In the Meis study (N Engl J Med. 2003;348:2379-85), treatment with 17-OHPC in women with a singleton gestation and a prior preterm delivery significantly reduced the risk of another preterm birth at less than 37 weeks’ gestation (36.3% in the progesterone group vs. 54.9% in the placebo group; relative risk, 0.66), at less than 35 weeks’ gestation (RR, 0.67), and at less than 32 weeks’ gestation (RR, 0.58). The exceptionally high rate of preterm delivery in the placebo group, however, prompted other investigators to express concern in published correspondence that the study was potentially flawed.

We reported an inverse relationship between 17-OHPC concentration and spontaneous preterm birth as part of a study conducted with the MFMU Network and the Obstetrical-Fetal Pharmacology Research Units Network. All women in the study had singleton gestations and received 250 mg weekly 17-OHPC (the broader study was designed to evaluate the benefit of omega-3 supplementation). We measured plasma concentrations of 17-OHPC and found that women with concentrations in the lowest quartile had a significantly higher risk of preterm birth and delivered at significantly earlier gestational ages than did women in the second through fourth quartiles (Am J Obstet Gynecol. 2014;210[2]:128.e1-6).

Other studies/abstracts similarly evaluating the relationship between 17-OHPC concentrations and preterm birth have reported mixed results, with both validation and refutation of our findings.

Research underway may help settle the controversy. In an ongoing, open-label pharmacology study being conducted by the Obstetrical-Fetal Pharmacology Research Units Network, women with singleton pregnancies and a history of prior preterm birth are being randomly assigned to receive either 250 mg (the empirically chosen, currently recommended dose) or 500 mg 17-OHPC. A relationship between the plasma concentration of 17-OHPC at 26-30 weeks’ gestation and the incidence of preterm birth would offer proof of efficacy and could help elucidate the therapeutic dosing; if there is no relationship, we revert to the question of whether the agent really works. Based on current evidence, both the Society for Maternal-Fetal Medicine (SMFM) and the American College of Obstetricians and Gynecologists (ACOG) support the use of 17-OHPC for prevention of sPTB in women with a prior sPTB.

Questions about vaginal progesterone have also been somewhat unsettled. Eduardo B. Fonseca, MD, reported in 2007 that asymptomatic women with a short cervix (defined as 15 mm or less) who were randomized to receive vaginal progesterone at a median of 22 weeks’ gestation had a significantly lower rate of preterm birth before 34 weeks’ gestation than those who received placebo (RR, 0.56; N Engl J Med. 2007;357[5]:462-9). Research that followed offered mixed conclusions, with a study by Sonia S. Hassan, MD, showing benefit and a study by Jane E. Norman, MD, showing no benefit. Notably, in 2012, the Food and Drug Administration voted against approval of a sustained-release progesterone vaginal gel, citing research results that were not sufficiently compelling.

Still, vaginal progesterone has been endorsed by both ACOG and by the SMFM for women with a short cervical length in the midtrimester. This is supported by a new review and meta-analysis of individual patient data by Roberto Romero, MD, in which vaginal progesterone was found to significantly decrease the risk of preterm birth in singleton gestations with a midtrimester cervical length of 25 mm or less. The reduction occurred over a wide range of gestational ages, including at less than 33 weeks of gestation (RR, 0.62; Am J Obstet Gynecol. 2018 Feb;218[2]:161-80).
 

Disagreement

Some have argued that vaginal progesterone should be offered to women with a history of prior spontaneous preterm birth, but the largest study to look at this application – a randomized multinational trial reported by John M. O’Brien, MD, and his colleagues in 2007 – found that use of the compound did not reduce the frequency of recurrent preterm birth at or before 32 weeks. Others have argued that vaginal progesterone is of benefit in this group of women based on a combination of multiple subgroup analyses. There is disagreement between ACOG and SMFM on this issue. ACOG supports the use of vaginal progesterone for women with a prior preterm birth but the SMFM strongly rejects this treatment and only endorses 17-OHPC for this indication.

Unresolved

The value of vaginal progesterone supplementation in reducing preterm births in women with twin gestations is under continuing investigation, including a study of women with twin gestation and a short cervix. This MFMU Network randomized trial, now underway, is evaluating the effectiveness of vaginal progesterone or pessary, compared with placebo, in preventing early preterm birth in women carrying twins who have a cervical length less than 30 mm.

Another question about the use of progesterone concerns the woman who delivered preterm during a twin gestation and is now pregnant with a singleton gestation. Should anything be offered to her? This is a question that has not yet been addressed in the literature.

What does seem clear is that spontaneous preterm birth is a multifactorial condition with numerous causes, and quite possibly an interaction between genetics, maternal characteristics, and the environment surrounding each pregnancy (Semin Perinatol. 2016;40[5]:273-80). Certainly, there are different pathways and mechanisms at play in patients who deliver at 35-36 weeks, for instance, compared with those who deliver at 25-26 weeks.

We recently obtained cervical fluid from pregnant women with prior preterm births and analyzed the samples for concentrations of cytokines and matrix metalloproteinases. Women with a prior early preterm delivery at less than 26 weeks had elevations in five cervical cytokines – an inflammatory signature, in essence – while those whose prior preterm birth occurred at a later gestational age had no elevations of these cytokines (Am J Perinatol. 2017 Nov 15. doi: 10.1055/s-0037-1608631).

Hopefully, we soon will be able to identify subpopulations of pregnant women who will benefit more from progesterone supplementation. More research needs to be done at a granular level, with more narrowly defined populations – and with consideration of various pharmacologic, genetic and environmental factors – in order to develop a more specific treatment approach. In the meantime, it is important to appreciate the unknowns that underlie the highly variable clinical responses and outcomes seen in our clinical trials.

Dr. Caritis is professor of obstetrics, gynecology, and reproductive sciences at Magee-Womens Hospital, University of Pittsburgh. He has no disclosures relevant to this Master Class.

In 2003, the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Maternal-Fetal Medicine Units (MFMU) Network reported on a placebo-controlled randomized study of 17–alpha hydroxyprogesterone caproate (17-OHPC) in women with a history of spontaneous preterm delivery. The study demonstrated a 33% reduction in recurrent preterm birth after weekly treatment with 17-OHPC, which was initiated at 16-20 weeks of gestation.

This landmark study, led by Paul Meis, MD, validated what had been suggested in an earlier meta-analysis (1990) by Mark Keirse, MD – and it quickly altered clinical practice. It set into motion a string of studies on the use of 17-OHPC and other progestational compounds in women with a variety of conditions associated with an increased risk for preterm birth.

Consensus

One area in which there is agreement concerns the use of 17-OHPC intramuscular injections in multifetal gestations. Two randomized clinical trials undertaken by the MFMU Network – one in twins and one in triplets – concluded that 17-OHPC is ineffective in reducing the rate of preterm birth. Moreover, in another, more recent MFMU Network study, there was a negative linear relationship between concentrations of 17-OHPC and gestational age at delivery. Women with twin gestations who had higher concentrations of 17-OHPC delivered at earlier gestational ages than women with lower concentrations (Am J Obstet Gynecol. 2012;207[5]:396.e1-8).

Other investigators have similarly shown in clinical trials that the preterm birth rate actually seems to be worsened in multifetal gestations when 17-OHPC is used. There is now widespread agreement that the compound should not be used in these patients.

In addition, an MFMU Network study led by William A. Grobman, MD, demonstrated that 17-OHPC (250-mg injections) does not provide any benefit to nulliparous women with a sonographic cervical length less than 30 mm (Am J Obstet Gynecol. 2012;207[5]:390.e1-8). Other studies utilizing higher doses of 17-OHPC similarly found no benefit. There is also agreement that 17-OHPC has no benefit in treating women with preterm premature rupture of the membranes, preterm labor, or as a maintenance treatment after an episode of preterm labor.

General agreement without consensus

There is general agreement that women with a singleton gestation and a prior spontaneous preterm birth should be offered 17-OHPC, and that women with a singleton gestation and a midtrimester shortened cervical length should be offered vaginal progesterone and not 17-OHPC. However, even in these populations, there are questions about efficacy, dosing, and other issues.

In the Meis study (N Engl J Med. 2003;348:2379-85), treatment with 17-OHPC in women with a singleton gestation and a prior preterm delivery significantly reduced the risk of another preterm birth at less than 37 weeks’ gestation (36.3% in the progesterone group vs. 54.9% in the placebo group; relative risk, 0.66), at less than 35 weeks’ gestation (RR, 0.67), and at less than 32 weeks’ gestation (RR, 0.58). The exceptionally high rate of preterm delivery in the placebo group, however, prompted other investigators to express concern in published correspondence that the study was potentially flawed.

We reported an inverse relationship between 17-OHPC concentration and spontaneous preterm birth as part of a study conducted with the MFMU Network and the Obstetrical-Fetal Pharmacology Research Units Network. All women in the study had singleton gestations and received 250 mg weekly 17-OHPC (the broader study was designed to evaluate the benefit of omega-3 supplementation). We measured plasma concentrations of 17-OHPC and found that women with concentrations in the lowest quartile had a significantly higher risk of preterm birth and delivered at significantly earlier gestational ages than did women in the second through fourth quartiles (Am J Obstet Gynecol. 2014;210[2]:128.e1-6).

Other studies/abstracts similarly evaluating the relationship between 17-OHPC concentrations and preterm birth have reported mixed results, with both validation and refutation of our findings.

Research underway may help settle the controversy. In an ongoing, open-label pharmacology study being conducted by the Obstetrical-Fetal Pharmacology Research Units Network, women with singleton pregnancies and a history of prior preterm birth are being randomly assigned to receive either 250 mg (the empirically chosen, currently recommended dose) or 500 mg 17-OHPC. A relationship between the plasma concentration of 17-OHPC at 26-30 weeks’ gestation and the incidence of preterm birth would offer proof of efficacy and could help elucidate the therapeutic dosing; if there is no relationship, we revert to the question of whether the agent really works. Based on current evidence, both the Society for Maternal-Fetal Medicine (SMFM) and the American College of Obstetricians and Gynecologists (ACOG) support the use of 17-OHPC for prevention of sPTB in women with a prior sPTB.

Questions about vaginal progesterone have also been somewhat unsettled. Eduardo B. Fonseca, MD, reported in 2007 that asymptomatic women with a short cervix (defined as 15 mm or less) who were randomized to receive vaginal progesterone at a median of 22 weeks’ gestation had a significantly lower rate of preterm birth before 34 weeks’ gestation than those who received placebo (RR, 0.56; N Engl J Med. 2007;357[5]:462-9). Research that followed offered mixed conclusions, with a study by Sonia S. Hassan, MD, showing benefit and a study by Jane E. Norman, MD, showing no benefit. Notably, in 2012, the Food and Drug Administration voted against approval of a sustained-release progesterone vaginal gel, citing research results that were not sufficiently compelling.

Still, vaginal progesterone has been endorsed by both ACOG and by the SMFM for women with a short cervical length in the midtrimester. This is supported by a new review and meta-analysis of individual patient data by Roberto Romero, MD, in which vaginal progesterone was found to significantly decrease the risk of preterm birth in singleton gestations with a midtrimester cervical length of 25 mm or less. The reduction occurred over a wide range of gestational ages, including at less than 33 weeks of gestation (RR, 0.62; Am J Obstet Gynecol. 2018 Feb;218[2]:161-80).
 

Disagreement

Some have argued that vaginal progesterone should be offered to women with a history of prior spontaneous preterm birth, but the largest study to look at this application – a randomized multinational trial reported by John M. O’Brien, MD, and his colleagues in 2007 – found that use of the compound did not reduce the frequency of recurrent preterm birth at or before 32 weeks. Others have argued that vaginal progesterone is of benefit in this group of women based on a combination of multiple subgroup analyses. There is disagreement between ACOG and SMFM on this issue. ACOG supports the use of vaginal progesterone for women with a prior preterm birth but the SMFM strongly rejects this treatment and only endorses 17-OHPC for this indication.

Unresolved

The value of vaginal progesterone supplementation in reducing preterm births in women with twin gestations is under continuing investigation, including a study of women with twin gestation and a short cervix. This MFMU Network randomized trial, now underway, is evaluating the effectiveness of vaginal progesterone or pessary, compared with placebo, in preventing early preterm birth in women carrying twins who have a cervical length less than 30 mm.

Another question about the use of progesterone concerns the woman who delivered preterm during a twin gestation and is now pregnant with a singleton gestation. Should anything be offered to her? This is a question that has not yet been addressed in the literature.

What does seem clear is that spontaneous preterm birth is a multifactorial condition with numerous causes, and quite possibly an interaction between genetics, maternal characteristics, and the environment surrounding each pregnancy (Semin Perinatol. 2016;40[5]:273-80). Certainly, there are different pathways and mechanisms at play in patients who deliver at 35-36 weeks, for instance, compared with those who deliver at 25-26 weeks.

We recently obtained cervical fluid from pregnant women with prior preterm births and analyzed the samples for concentrations of cytokines and matrix metalloproteinases. Women with a prior early preterm delivery at less than 26 weeks had elevations in five cervical cytokines – an inflammatory signature, in essence – while those whose prior preterm birth occurred at a later gestational age had no elevations of these cytokines (Am J Perinatol. 2017 Nov 15. doi: 10.1055/s-0037-1608631).

Hopefully, we soon will be able to identify subpopulations of pregnant women who will benefit more from progesterone supplementation. More research needs to be done at a granular level, with more narrowly defined populations – and with consideration of various pharmacologic, genetic and environmental factors – in order to develop a more specific treatment approach. In the meantime, it is important to appreciate the unknowns that underlie the highly variable clinical responses and outcomes seen in our clinical trials.

Dr. Caritis is professor of obstetrics, gynecology, and reproductive sciences at Magee-Womens Hospital, University of Pittsburgh. He has no disclosures relevant to this Master Class.