Patrice Wendling

LISBON – Dilation and curettage increases the risk for prematurity in subsequent pregnancy, according to a systematic review and meta-analysis of nearly 2 million women.

Overall, D&C for first-trimester miscarriage or pregnancy termination increased the risk for preterm birth (< 37 weeks) by 29% (Odds ratio, 1.29; 95% confidence interval 1.17-1.42).

Subgroup and sensitivity analyses performed to test the robustness of the finding showed D&C upped the risk for very preterm birth (< 32 weeks) by 69% (OR, 1.69; C.I. 1.20-2.38) and critical preterm birth (< 28 weeks) by 68% (OR, 1.68; C.I. 1.47-1.92).

Patrice Wendling/Frontline Medical News

A dose-response relationship was also identified, with multiple D&C procedures raising the risk of preterm birth even higher (OR, 1.74; C.I. 1.10-2.76), Dr. Marike Lemmers reported at the annual meeting of the European Society of Human Reproduction and Embryology.

“This really questions the use of dilation and curettage as first-line treatment for women with a miscarriage or termination of pregnancy since other treatment options are non-invasive, safe, well-tolerated, cheap, and accessible,” Dr. Lemmers, of the Academic Medical Center, Amsterdam, the Netherlands, said.

The increasing popularity of misoprostol as an alternative to D&C or for cervical priming prior to curettage would suggest that D&C use is declining. Still, gynecologists in the Netherlands treat half of all miscarriages with D&C, a figure that likely reflects practice elsewhere, Dr. Willem Ankum, the principal investigator, said during a press briefing.

The authors hypothesize that the mechanism behind the increased risk from D&C is that dilation may damage the cervix and affect cervical tightness or may damage the endometrial lining, leading to a malpresentation.

The systematic review and meta-analysis included 21 studies (7 prospective cohort studies, 11 retrospective cohort studies, and 3 case-control studies) involving 66,003 women with a history of D&C for first trimester miscarriage or termination, and 1,781,786 controls with a medically managed miscarriage or termination or no such events. The quality of the studies varied from 7 to 29 based on the Strobe score.

The primary outcome of risk of preterm birth was significantly increased with D&C regardless of whether the analysis relied only on the prospective studies (OR, 1.28; C.I. 1.01-1.60), retrospective studies (OR, 1.27; C.I. 1.12-1.45), or case-control studies (OR, 1.44; C.I. 1.18-1.77), Dr. Lemmers said.

Several audience members questioned the inclusion of older trials dating back to the late 1970s before prostoglandins had been introduced for cycle priming. One attendee cited a recent Scottish cohort study showing a declining preterm birth rate in women with previous miscarriage, possibly attributable to the increasing use of misoprostol (Cytotec) for miscarriage or termination and cervical priming before D&C (PLoS. Med. 2013; 10: e1001481 [doi:10.1371/journal.pmed.1001481]).

Dr. Lemmers was aware of the Scottish study and said a funnel plot they performed showed “the exact same results” between older and newer studies. Further, a subgroup analysis of 38,905 women from studies dating from 1999 forward also showed an increased risk of preterm birth with D&C versus medical treatment (OR, 1.19; C.I. 1.10-1.28).

She added that it’s unlikely that the use of hysteroscopy with minimal dilation before in-vitro fertilization impacted results, but that outcomes may differ between women with a miscarriage versus termination of an attached pregnancy, although this calculation wasn’t possible based on the available data.

ZonMw, a Dutch organization for health research and development, funded the study. Dr. Lemmers and Dr. Ankum reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Dilation and curettage increases the risk for prematurity in subsequent pregnancy, according to a systematic review and meta-analysis of nearly 2 million women.

Overall, D&C for first-trimester miscarriage or pregnancy termination increased the risk for preterm birth (< 37 weeks) by 29% (Odds ratio, 1.29; 95% confidence interval 1.17-1.42).

Subgroup and sensitivity analyses performed to test the robustness of the finding showed D&C upped the risk for very preterm birth (< 32 weeks) by 69% (OR, 1.69; C.I. 1.20-2.38) and critical preterm birth (< 28 weeks) by 68% (OR, 1.68; C.I. 1.47-1.92).

Patrice Wendling/Frontline Medical News

A dose-response relationship was also identified, with multiple D&C procedures raising the risk of preterm birth even higher (OR, 1.74; C.I. 1.10-2.76), Dr. Marike Lemmers reported at the annual meeting of the European Society of Human Reproduction and Embryology.

“This really questions the use of dilation and curettage as first-line treatment for women with a miscarriage or termination of pregnancy since other treatment options are non-invasive, safe, well-tolerated, cheap, and accessible,” Dr. Lemmers, of the Academic Medical Center, Amsterdam, the Netherlands, said.

The increasing popularity of misoprostol as an alternative to D&C or for cervical priming prior to curettage would suggest that D&C use is declining. Still, gynecologists in the Netherlands treat half of all miscarriages with D&C, a figure that likely reflects practice elsewhere, Dr. Willem Ankum, the principal investigator, said during a press briefing.

The authors hypothesize that the mechanism behind the increased risk from D&C is that dilation may damage the cervix and affect cervical tightness or may damage the endometrial lining, leading to a malpresentation.

The systematic review and meta-analysis included 21 studies (7 prospective cohort studies, 11 retrospective cohort studies, and 3 case-control studies) involving 66,003 women with a history of D&C for first trimester miscarriage or termination, and 1,781,786 controls with a medically managed miscarriage or termination or no such events. The quality of the studies varied from 7 to 29 based on the Strobe score.

The primary outcome of risk of preterm birth was significantly increased with D&C regardless of whether the analysis relied only on the prospective studies (OR, 1.28; C.I. 1.01-1.60), retrospective studies (OR, 1.27; C.I. 1.12-1.45), or case-control studies (OR, 1.44; C.I. 1.18-1.77), Dr. Lemmers said.

Several audience members questioned the inclusion of older trials dating back to the late 1970s before prostoglandins had been introduced for cycle priming. One attendee cited a recent Scottish cohort study showing a declining preterm birth rate in women with previous miscarriage, possibly attributable to the increasing use of misoprostol (Cytotec) for miscarriage or termination and cervical priming before D&C (PLoS. Med. 2013; 10: e1001481 [doi:10.1371/journal.pmed.1001481]).

Dr. Lemmers was aware of the Scottish study and said a funnel plot they performed showed “the exact same results” between older and newer studies. Further, a subgroup analysis of 38,905 women from studies dating from 1999 forward also showed an increased risk of preterm birth with D&C versus medical treatment (OR, 1.19; C.I. 1.10-1.28).

She added that it’s unlikely that the use of hysteroscopy with minimal dilation before in-vitro fertilization impacted results, but that outcomes may differ between women with a miscarriage versus termination of an attached pregnancy, although this calculation wasn’t possible based on the available data.

ZonMw, a Dutch organization for health research and development, funded the study. Dr. Lemmers and Dr. Ankum reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Dilation and curettage increases the risk for prematurity in subsequent pregnancy, according to a systematic review and meta-analysis of nearly 2 million women.

Overall, D&C for first-trimester miscarriage or pregnancy termination increased the risk for preterm birth (< 37 weeks) by 29% (Odds ratio, 1.29; 95% confidence interval 1.17-1.42).

Subgroup and sensitivity analyses performed to test the robustness of the finding showed D&C upped the risk for very preterm birth (< 32 weeks) by 69% (OR, 1.69; C.I. 1.20-2.38) and critical preterm birth (< 28 weeks) by 68% (OR, 1.68; C.I. 1.47-1.92).

Patrice Wendling/Frontline Medical News

A dose-response relationship was also identified, with multiple D&C procedures raising the risk of preterm birth even higher (OR, 1.74; C.I. 1.10-2.76), Dr. Marike Lemmers reported at the annual meeting of the European Society of Human Reproduction and Embryology.

“This really questions the use of dilation and curettage as first-line treatment for women with a miscarriage or termination of pregnancy since other treatment options are non-invasive, safe, well-tolerated, cheap, and accessible,” Dr. Lemmers, of the Academic Medical Center, Amsterdam, the Netherlands, said.

The increasing popularity of misoprostol as an alternative to D&C or for cervical priming prior to curettage would suggest that D&C use is declining. Still, gynecologists in the Netherlands treat half of all miscarriages with D&C, a figure that likely reflects practice elsewhere, Dr. Willem Ankum, the principal investigator, said during a press briefing.

The authors hypothesize that the mechanism behind the increased risk from D&C is that dilation may damage the cervix and affect cervical tightness or may damage the endometrial lining, leading to a malpresentation.

The systematic review and meta-analysis included 21 studies (7 prospective cohort studies, 11 retrospective cohort studies, and 3 case-control studies) involving 66,003 women with a history of D&C for first trimester miscarriage or termination, and 1,781,786 controls with a medically managed miscarriage or termination or no such events. The quality of the studies varied from 7 to 29 based on the Strobe score.

The primary outcome of risk of preterm birth was significantly increased with D&C regardless of whether the analysis relied only on the prospective studies (OR, 1.28; C.I. 1.01-1.60), retrospective studies (OR, 1.27; C.I. 1.12-1.45), or case-control studies (OR, 1.44; C.I. 1.18-1.77), Dr. Lemmers said.

Several audience members questioned the inclusion of older trials dating back to the late 1970s before prostoglandins had been introduced for cycle priming. One attendee cited a recent Scottish cohort study showing a declining preterm birth rate in women with previous miscarriage, possibly attributable to the increasing use of misoprostol (Cytotec) for miscarriage or termination and cervical priming before D&C (PLoS. Med. 2013; 10: e1001481 [doi:10.1371/journal.pmed.1001481]).

Dr. Lemmers was aware of the Scottish study and said a funnel plot they performed showed “the exact same results” between older and newer studies. Further, a subgroup analysis of 38,905 women from studies dating from 1999 forward also showed an increased risk of preterm birth with D&C versus medical treatment (OR, 1.19; C.I. 1.10-1.28).

She added that it’s unlikely that the use of hysteroscopy with minimal dilation before in-vitro fertilization impacted results, but that outcomes may differ between women with a miscarriage versus termination of an attached pregnancy, although this calculation wasn’t possible based on the available data.

ZonMw, a Dutch organization for health research and development, funded the study. Dr. Lemmers and Dr. Ankum reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Expectant management is a safe and effective treatment for incomplete miscarriage after misoprostol, results of the MisoREST trial show.

“Because it is non-invasive, we think it should be considered as first-line treatment and to reserve curettage only for specific patients,” Dr. Marianne Verschoor said at the annual meeting of the European Society of Human Reproduction and Embryology.

Patrice Wendling/Frontline Medical News

Misoprostol (Cytotec) is an inexpensive and effective treatment for miscarriage, but about 30% of women are left with an incomplete evacuation of the uterus. Curettage is often performed in these typically asymptomatic women, but carries both short- and long-term risks, said Dr. Verschoor of the Academic Medical Center, Amsterdam.

No study had directly compared the effectiveness of curettage and expectant management, she said. To fill this void, the researchers performed a randomized controlled trial (RCT) and parallel observational cohort study at 27 community and academic hospitals. Women who had sonographic findings of intrauterine remnants and/or a thick endometrium (> 10 mm) 1-2 weeks after misoprostol treatment for first-trimester miscarriage were randomly assigned to curettage within 3 days of diagnosis or expectant management. Women who declined randomization were prospectively followed.

The primary outcome was sonographic evidence of an empty uterine cavity at 6 weeks or an uneventful clinical course at 3 months in the absence of sonography.

Because of strong preferences for expectant management (EM), 59 women were randomized in the RCT (30 curettage, 29 EM) and 197 women were followed prospectively (65 curettage, 132 EM). All groups were comparable at baseline with regard to age, gestational age, and previous miscarriage or curettage.

In the RCT, 93% of women had an empty cavity or uneventful clinical course with curettage vs. 76% with EM. This difference was not statistically significant (relative risk, 1.23; 95% confidence interval, 0.098-1.54), Dr. Verschoor said.

In the observational cohort, 95% of patients choosing curettage had a successful outcome vs. 83% choosing EM. This difference was statistically significant (RR, 1.14; CI, 1.04-1.26).

When the two populations were pooled, 95% of patients (90/95) treated with curettage reached the primary end point vs. 82% of patients (132/161) with EM, which was statistically different (RR, 1.16; CI, 1.06-1.26), she said.

There were no significant differences in secondary outcomes in the RCT between the curettage and EM groups, including intrauterine infection (each 1 patient), excessive blood loss defined as > 500 mL (1 patient vs. 2 patients), or duration of bleeding (mean 5.4 days vs. 5.5 days).

However, one patient had already developed Asherman syndrome in the curettage group within 3 months of follow-up, Dr. Verschoor said. Two patients in each arm underwent reintervention with hysteroscopy and 5 EM patients underwent curettage.

Secondary outcomes in the observational cohort were also comparable between the curettage and EM groups for intrauterine infection (3 vs. 2), excessive blood loss (0 vs. 1), and duration of bleeding (mean 5.7 days vs. 7.1 days). One patient who underwent curettage developed Asherman syndrome vs. none in the EM group, she said. There were 11 reinterventions in the curettage group (7 hysteroscopy, 4 recurettage), compared with 30 in the EM group (12 hysteroscopy, 18 curettage).

A closer look at the EM patients who underwent reintervention revealed that “the interventions were primarily elective,” Dr. Vershcoor said. “Only in 26% of cases was there a medical reason for performing the intervention like bleeding, fever, or excessive abdominal pain.” Histology performed in these patients found no pregnancy tissue in 46%.

A separate quality of life analysis of the MisoREST participants found no statistical differences at baseline, 2, 4, and 12 weeks for the Short Form 36 Health Survey mental and physical score in all four treatment arms. Anxiety and depression measured with the Hospital Anxiety and Depression Scale were also not statistically different at any time, study coauthor Dr. Marike Lemmers, also of the Academic Medical Center, Amsterdam, reported in a poster at the meeting.

ZonMw, a Dutch organization for health research and development, funded the study. Dr. Verschoor reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Expectant management is a safe and effective treatment for incomplete miscarriage after misoprostol, results of the MisoREST trial show.

“Because it is non-invasive, we think it should be considered as first-line treatment and to reserve curettage only for specific patients,” Dr. Marianne Verschoor said at the annual meeting of the European Society of Human Reproduction and Embryology.

Patrice Wendling/Frontline Medical News

Misoprostol (Cytotec) is an inexpensive and effective treatment for miscarriage, but about 30% of women are left with an incomplete evacuation of the uterus. Curettage is often performed in these typically asymptomatic women, but carries both short- and long-term risks, said Dr. Verschoor of the Academic Medical Center, Amsterdam.

No study had directly compared the effectiveness of curettage and expectant management, she said. To fill this void, the researchers performed a randomized controlled trial (RCT) and parallel observational cohort study at 27 community and academic hospitals. Women who had sonographic findings of intrauterine remnants and/or a thick endometrium (> 10 mm) 1-2 weeks after misoprostol treatment for first-trimester miscarriage were randomly assigned to curettage within 3 days of diagnosis or expectant management. Women who declined randomization were prospectively followed.

The primary outcome was sonographic evidence of an empty uterine cavity at 6 weeks or an uneventful clinical course at 3 months in the absence of sonography.

Because of strong preferences for expectant management (EM), 59 women were randomized in the RCT (30 curettage, 29 EM) and 197 women were followed prospectively (65 curettage, 132 EM). All groups were comparable at baseline with regard to age, gestational age, and previous miscarriage or curettage.

In the RCT, 93% of women had an empty cavity or uneventful clinical course with curettage vs. 76% with EM. This difference was not statistically significant (relative risk, 1.23; 95% confidence interval, 0.098-1.54), Dr. Verschoor said.

In the observational cohort, 95% of patients choosing curettage had a successful outcome vs. 83% choosing EM. This difference was statistically significant (RR, 1.14; CI, 1.04-1.26).

When the two populations were pooled, 95% of patients (90/95) treated with curettage reached the primary end point vs. 82% of patients (132/161) with EM, which was statistically different (RR, 1.16; CI, 1.06-1.26), she said.

There were no significant differences in secondary outcomes in the RCT between the curettage and EM groups, including intrauterine infection (each 1 patient), excessive blood loss defined as > 500 mL (1 patient vs. 2 patients), or duration of bleeding (mean 5.4 days vs. 5.5 days).

However, one patient had already developed Asherman syndrome in the curettage group within 3 months of follow-up, Dr. Verschoor said. Two patients in each arm underwent reintervention with hysteroscopy and 5 EM patients underwent curettage.

Secondary outcomes in the observational cohort were also comparable between the curettage and EM groups for intrauterine infection (3 vs. 2), excessive blood loss (0 vs. 1), and duration of bleeding (mean 5.7 days vs. 7.1 days). One patient who underwent curettage developed Asherman syndrome vs. none in the EM group, she said. There were 11 reinterventions in the curettage group (7 hysteroscopy, 4 recurettage), compared with 30 in the EM group (12 hysteroscopy, 18 curettage).

A closer look at the EM patients who underwent reintervention revealed that “the interventions were primarily elective,” Dr. Vershcoor said. “Only in 26% of cases was there a medical reason for performing the intervention like bleeding, fever, or excessive abdominal pain.” Histology performed in these patients found no pregnancy tissue in 46%.

A separate quality of life analysis of the MisoREST participants found no statistical differences at baseline, 2, 4, and 12 weeks for the Short Form 36 Health Survey mental and physical score in all four treatment arms. Anxiety and depression measured with the Hospital Anxiety and Depression Scale were also not statistically different at any time, study coauthor Dr. Marike Lemmers, also of the Academic Medical Center, Amsterdam, reported in a poster at the meeting.

ZonMw, a Dutch organization for health research and development, funded the study. Dr. Verschoor reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Expectant management is a safe and effective treatment for incomplete miscarriage after misoprostol, results of the MisoREST trial show.

“Because it is non-invasive, we think it should be considered as first-line treatment and to reserve curettage only for specific patients,” Dr. Marianne Verschoor said at the annual meeting of the European Society of Human Reproduction and Embryology.

Patrice Wendling/Frontline Medical News

Misoprostol (Cytotec) is an inexpensive and effective treatment for miscarriage, but about 30% of women are left with an incomplete evacuation of the uterus. Curettage is often performed in these typically asymptomatic women, but carries both short- and long-term risks, said Dr. Verschoor of the Academic Medical Center, Amsterdam.

No study had directly compared the effectiveness of curettage and expectant management, she said. To fill this void, the researchers performed a randomized controlled trial (RCT) and parallel observational cohort study at 27 community and academic hospitals. Women who had sonographic findings of intrauterine remnants and/or a thick endometrium (> 10 mm) 1-2 weeks after misoprostol treatment for first-trimester miscarriage were randomly assigned to curettage within 3 days of diagnosis or expectant management. Women who declined randomization were prospectively followed.

The primary outcome was sonographic evidence of an empty uterine cavity at 6 weeks or an uneventful clinical course at 3 months in the absence of sonography.

Because of strong preferences for expectant management (EM), 59 women were randomized in the RCT (30 curettage, 29 EM) and 197 women were followed prospectively (65 curettage, 132 EM). All groups were comparable at baseline with regard to age, gestational age, and previous miscarriage or curettage.

In the RCT, 93% of women had an empty cavity or uneventful clinical course with curettage vs. 76% with EM. This difference was not statistically significant (relative risk, 1.23; 95% confidence interval, 0.098-1.54), Dr. Verschoor said.

In the observational cohort, 95% of patients choosing curettage had a successful outcome vs. 83% choosing EM. This difference was statistically significant (RR, 1.14; CI, 1.04-1.26).

When the two populations were pooled, 95% of patients (90/95) treated with curettage reached the primary end point vs. 82% of patients (132/161) with EM, which was statistically different (RR, 1.16; CI, 1.06-1.26), she said.

There were no significant differences in secondary outcomes in the RCT between the curettage and EM groups, including intrauterine infection (each 1 patient), excessive blood loss defined as > 500 mL (1 patient vs. 2 patients), or duration of bleeding (mean 5.4 days vs. 5.5 days).

However, one patient had already developed Asherman syndrome in the curettage group within 3 months of follow-up, Dr. Verschoor said. Two patients in each arm underwent reintervention with hysteroscopy and 5 EM patients underwent curettage.

Secondary outcomes in the observational cohort were also comparable between the curettage and EM groups for intrauterine infection (3 vs. 2), excessive blood loss (0 vs. 1), and duration of bleeding (mean 5.7 days vs. 7.1 days). One patient who underwent curettage developed Asherman syndrome vs. none in the EM group, she said. There were 11 reinterventions in the curettage group (7 hysteroscopy, 4 recurettage), compared with 30 in the EM group (12 hysteroscopy, 18 curettage).

A closer look at the EM patients who underwent reintervention revealed that “the interventions were primarily elective,” Dr. Vershcoor said. “Only in 26% of cases was there a medical reason for performing the intervention like bleeding, fever, or excessive abdominal pain.” Histology performed in these patients found no pregnancy tissue in 46%.

A separate quality of life analysis of the MisoREST participants found no statistical differences at baseline, 2, 4, and 12 weeks for the Short Form 36 Health Survey mental and physical score in all four treatment arms. Anxiety and depression measured with the Hospital Anxiety and Depression Scale were also not statistically different at any time, study coauthor Dr. Marike Lemmers, also of the Academic Medical Center, Amsterdam, reported in a poster at the meeting.

ZonMw, a Dutch organization for health research and development, funded the study. Dr. Verschoor reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Advanced age appears to trump disease activity or antirheumatic drug treatment as the driving force behind miscarriage in women with rheumatoid arthritis.

“The risk for miscarriage in rheumatoid arthritis is age dependent,” Dr. Jenny Brouwer said at the annual meeting of the European Society of Human Reproduction and Embryology.

Patrice Wendling/Frontline Medical News

She reported on 162 evaluable pregnancies in 239 Dutch women enrolled during 2002-2010 in the nationwide Pregnancy-Induced Amelioration of Rheumatoid Arthritis (PARA) study, the world’s largest prospective cohort of pregnant RA patients. They had a mean age of 32.3 years and a mean RA duration of 4.9 years. Overall, 49.4% were nulliparous and 13.6% had suffered a previous miscarriage.

Prednisone (37%), sulfasalazine (33%), and NSAIDs (29%) were most commonly used in the periconceptional period. Women eligible for PARA had to have stopped methotrexate for at least 3 months prior to attempting to conceive, a parameter included because it is an indicator for more severe disease.

Varying reports have shown no increased miscarriage rate in women with RA, while others have reported a significantly higher risk. These studies, however, were cross-sectional or retrospective in nature and lacked detailed information on preconception disease activity and antirheumatic drug use, observed Dr. Brouwer of Erasmus Medical Center, Rotterdam, the Netherlands.

Among the 162 pregnancies, 28 miscarriages occurred (17.3%), roughly half in weeks 5-9.

Reassuringly, the miscarriage rate is comparable with that in the general population, she said. Indeed, a recent study from the Nurses Health Study II also reported a miscarriage rate of 17.3%.

Disease Activity Score based on 28 joints (DAS28) was higher 6 and 12 weeks after miscarriage than before pregnancy, with 33% of women having a disease flare after miscarriage.

“This can be a sign that women who have more active disease have a higher risk for miscarriage and should be monitored more closely when their disease activity in the preconceptional period increases,” Dr. Brouwer said.

Women who miscarried were significantly older than were women with an ongoing pregnancy (mean 33.9 years vs. 32 years; P = .022). They also were more likely to be positive for anti-citrullinated protein antibodies (ACPA) (82% vs. 60%; P = .058), have higher DAS28 scores (3.92 vs. 3.59; P = .166), and have used methotrexate in the past (82% vs. 68%; P = .174).

No significant association was observed between miscarriage and corticosteroids, anti-inflammatories, or biological therapies, she said.

Because of the low frequency of miscarriages in the study, logistic regression showed only a trend toward higher miscarriage risk in association with increasing age (OR, 1.12; P = .065 per year of age increase) and ACPA positivity (OR, 2.47; P = .092), Dr. Brouwer said.

“Since the confidence interval is 0.99-1.25, there clearly seems to be a trend toward a higher risk for occurrence of miscarriage with increasing age, which is only logical since in the general population we also see an increase in miscarriage rate with increasing age,” she said in an interview. “My expectation is that, in a larger RA cohort, with a larger absolute number of miscarriages, the association will be significant.”

Follow-up revealed that, within 1 year of miscarriage, 68% of women became pregnant again, 14% stopped trying to conceive, and 11% were lost to follow-up. The live birth rate in the subsequent pregnancy was 90%. A follow-up study of these children did not find an increased rate of congenital malformations, despite the use of RA medications during pregnancy, Dr. Brouwer said.

The audience questioned whether the investigators are suggesting that rheumatoid arthritis has no role in miscarriage, observing that the study outcomes look very similar to patients without RA. Dr. Brouwer responded that there seems to be a higher sensitivity in patients with ACPA using methotrexate in the past but that this failed to reach significance.

“The results found in this study: some association with more severe disease – ACPA positivity and past methotrexate use – although not significant are a confirmation to us that extra care should be given to suppressing active disease already before actively trying to achieve a pregnancy,” she told this publication.

For more details, the full manuscript has been published (Arthritis Rheumatol. 2015;67:1738-43).

Reumafond, the Dutch Arthritis Foundation, funded the study. Dr. Brouwer reported no financial conflicts.

[email protected]

LISBON – Advanced age appears to trump disease activity or antirheumatic drug treatment as the driving force behind miscarriage in women with rheumatoid arthritis.

“The risk for miscarriage in rheumatoid arthritis is age dependent,” Dr. Jenny Brouwer said at the annual meeting of the European Society of Human Reproduction and Embryology.

Patrice Wendling/Frontline Medical News

She reported on 162 evaluable pregnancies in 239 Dutch women enrolled during 2002-2010 in the nationwide Pregnancy-Induced Amelioration of Rheumatoid Arthritis (PARA) study, the world’s largest prospective cohort of pregnant RA patients. They had a mean age of 32.3 years and a mean RA duration of 4.9 years. Overall, 49.4% were nulliparous and 13.6% had suffered a previous miscarriage.

Prednisone (37%), sulfasalazine (33%), and NSAIDs (29%) were most commonly used in the periconceptional period. Women eligible for PARA had to have stopped methotrexate for at least 3 months prior to attempting to conceive, a parameter included because it is an indicator for more severe disease.

Varying reports have shown no increased miscarriage rate in women with RA, while others have reported a significantly higher risk. These studies, however, were cross-sectional or retrospective in nature and lacked detailed information on preconception disease activity and antirheumatic drug use, observed Dr. Brouwer of Erasmus Medical Center, Rotterdam, the Netherlands.

Among the 162 pregnancies, 28 miscarriages occurred (17.3%), roughly half in weeks 5-9.

Reassuringly, the miscarriage rate is comparable with that in the general population, she said. Indeed, a recent study from the Nurses Health Study II also reported a miscarriage rate of 17.3%.

Disease Activity Score based on 28 joints (DAS28) was higher 6 and 12 weeks after miscarriage than before pregnancy, with 33% of women having a disease flare after miscarriage.

“This can be a sign that women who have more active disease have a higher risk for miscarriage and should be monitored more closely when their disease activity in the preconceptional period increases,” Dr. Brouwer said.

Women who miscarried were significantly older than were women with an ongoing pregnancy (mean 33.9 years vs. 32 years; P = .022). They also were more likely to be positive for anti-citrullinated protein antibodies (ACPA) (82% vs. 60%; P = .058), have higher DAS28 scores (3.92 vs. 3.59; P = .166), and have used methotrexate in the past (82% vs. 68%; P = .174).

No significant association was observed between miscarriage and corticosteroids, anti-inflammatories, or biological therapies, she said.

Because of the low frequency of miscarriages in the study, logistic regression showed only a trend toward higher miscarriage risk in association with increasing age (OR, 1.12; P = .065 per year of age increase) and ACPA positivity (OR, 2.47; P = .092), Dr. Brouwer said.

“Since the confidence interval is 0.99-1.25, there clearly seems to be a trend toward a higher risk for occurrence of miscarriage with increasing age, which is only logical since in the general population we also see an increase in miscarriage rate with increasing age,” she said in an interview. “My expectation is that, in a larger RA cohort, with a larger absolute number of miscarriages, the association will be significant.”

Follow-up revealed that, within 1 year of miscarriage, 68% of women became pregnant again, 14% stopped trying to conceive, and 11% were lost to follow-up. The live birth rate in the subsequent pregnancy was 90%. A follow-up study of these children did not find an increased rate of congenital malformations, despite the use of RA medications during pregnancy, Dr. Brouwer said.

The audience questioned whether the investigators are suggesting that rheumatoid arthritis has no role in miscarriage, observing that the study outcomes look very similar to patients without RA. Dr. Brouwer responded that there seems to be a higher sensitivity in patients with ACPA using methotrexate in the past but that this failed to reach significance.

“The results found in this study: some association with more severe disease – ACPA positivity and past methotrexate use – although not significant are a confirmation to us that extra care should be given to suppressing active disease already before actively trying to achieve a pregnancy,” she told this publication.

For more details, the full manuscript has been published (Arthritis Rheumatol. 2015;67:1738-43).

Reumafond, the Dutch Arthritis Foundation, funded the study. Dr. Brouwer reported no financial conflicts.

[email protected]

LISBON – Advanced age appears to trump disease activity or antirheumatic drug treatment as the driving force behind miscarriage in women with rheumatoid arthritis.

“The risk for miscarriage in rheumatoid arthritis is age dependent,” Dr. Jenny Brouwer said at the annual meeting of the European Society of Human Reproduction and Embryology.

Patrice Wendling/Frontline Medical News

She reported on 162 evaluable pregnancies in 239 Dutch women enrolled during 2002-2010 in the nationwide Pregnancy-Induced Amelioration of Rheumatoid Arthritis (PARA) study, the world’s largest prospective cohort of pregnant RA patients. They had a mean age of 32.3 years and a mean RA duration of 4.9 years. Overall, 49.4% were nulliparous and 13.6% had suffered a previous miscarriage.

Prednisone (37%), sulfasalazine (33%), and NSAIDs (29%) were most commonly used in the periconceptional period. Women eligible for PARA had to have stopped methotrexate for at least 3 months prior to attempting to conceive, a parameter included because it is an indicator for more severe disease.

Varying reports have shown no increased miscarriage rate in women with RA, while others have reported a significantly higher risk. These studies, however, were cross-sectional or retrospective in nature and lacked detailed information on preconception disease activity and antirheumatic drug use, observed Dr. Brouwer of Erasmus Medical Center, Rotterdam, the Netherlands.

Among the 162 pregnancies, 28 miscarriages occurred (17.3%), roughly half in weeks 5-9.

Reassuringly, the miscarriage rate is comparable with that in the general population, she said. Indeed, a recent study from the Nurses Health Study II also reported a miscarriage rate of 17.3%.

Disease Activity Score based on 28 joints (DAS28) was higher 6 and 12 weeks after miscarriage than before pregnancy, with 33% of women having a disease flare after miscarriage.

“This can be a sign that women who have more active disease have a higher risk for miscarriage and should be monitored more closely when their disease activity in the preconceptional period increases,” Dr. Brouwer said.

Women who miscarried were significantly older than were women with an ongoing pregnancy (mean 33.9 years vs. 32 years; P = .022). They also were more likely to be positive for anti-citrullinated protein antibodies (ACPA) (82% vs. 60%; P = .058), have higher DAS28 scores (3.92 vs. 3.59; P = .166), and have used methotrexate in the past (82% vs. 68%; P = .174).

No significant association was observed between miscarriage and corticosteroids, anti-inflammatories, or biological therapies, she said.

Because of the low frequency of miscarriages in the study, logistic regression showed only a trend toward higher miscarriage risk in association with increasing age (OR, 1.12; P = .065 per year of age increase) and ACPA positivity (OR, 2.47; P = .092), Dr. Brouwer said.

“Since the confidence interval is 0.99-1.25, there clearly seems to be a trend toward a higher risk for occurrence of miscarriage with increasing age, which is only logical since in the general population we also see an increase in miscarriage rate with increasing age,” she said in an interview. “My expectation is that, in a larger RA cohort, with a larger absolute number of miscarriages, the association will be significant.”

Follow-up revealed that, within 1 year of miscarriage, 68% of women became pregnant again, 14% stopped trying to conceive, and 11% were lost to follow-up. The live birth rate in the subsequent pregnancy was 90%. A follow-up study of these children did not find an increased rate of congenital malformations, despite the use of RA medications during pregnancy, Dr. Brouwer said.

The audience questioned whether the investigators are suggesting that rheumatoid arthritis has no role in miscarriage, observing that the study outcomes look very similar to patients without RA. Dr. Brouwer responded that there seems to be a higher sensitivity in patients with ACPA using methotrexate in the past but that this failed to reach significance.

“The results found in this study: some association with more severe disease – ACPA positivity and past methotrexate use – although not significant are a confirmation to us that extra care should be given to suppressing active disease already before actively trying to achieve a pregnancy,” she told this publication.

For more details, the full manuscript has been published (Arthritis Rheumatol. 2015;67:1738-43).

Reumafond, the Dutch Arthritis Foundation, funded the study. Dr. Brouwer reported no financial conflicts.

[email protected]

LISBON – Women undergoing assisted reproduction had similar pregnancy rates with gonadotropin-releasing hormone agonist and antagonist protocols, but less ovarian hyperstimulation syndrome with the GnRH-antagonist protocol in a large randomized trial.

Severe ovarian hyperstimulation syndrome (OHSS) was roughly halved with the GnRH-antagonist vs. the GnRH-agonist protocol (3.2% vs. 6.1%; P = .03), as were ascites punctures (0 vs. 2%: P = .001) and treatment changes due to risk of OHSS (5.7% vs. 10.3%; P = .006).

Patrice Wendling/Frontline Medical News

Hospital admissions for OHSS also favored the GnRH antagonist protocol (1.7% vs. 3.6%; P = .06), Dr. Mette Toftager reported at the annual meeting of the European Society of Human Reproduction and Embryology.

The exact impact of these protocols has been controversial following early reports that GnRH antagonists were associated with lower pregnancy rates.

Two 2006 meta-analyses yielded conflicting results, but were based on small heterogeneous trials that were not powered for OHSS nor pregnancy rates and were conducted in selected populations, said Dr. Toftager of Fertility Clinic, Hvidovre Hospital, Denmark.

The current noninferiority trial used few inclusion criteria – just age 18-40 years and first in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle – to prospectively enroll 1,099 women and evenly randomize them to a classic short GnRH-antagonist protocol or a classic long GnRH-agonist protocol.

Women received a fixed dose of either recombinant follicle stimulating hormone 150 IU or 225 IU based on age (≤ 36 years vs. > 36 years) and were given the option to adjust the rFSH dose based on ovarian response at stimulation day 6.

The trial was designed to detect a 2.5% difference in moderate/severe OHSS per Golan OHSS criteria between the two groups, stratified by age, IVF center, and IVF/ICSI.

At baseline, the two groups were comparable in age (mean 32 years), cycle length (mean 28.9 days), and nulliparity (92.3%). The study included women with irregular cycles and polycystic ovary syndrome, who represented about 13% of each group.

Regarding stimulation, significant differences were found between the GnRH-antagonist and GnRH-agonist groups in total rFSH dose (mean 1,522 IU vs. 1,999 IU), days of stimulation (mean 9 vs. 11), and the number of aspirated oocytes (mean 8.5 vs. 10; P < .0001 for all), Dr. Toftager reported.

The GnRH-antagonist and GnRH-agonist groups had the same number of embryos transferred (mean 1.1 vs. 1.2), use of embryo freezing (50% vs. 53%), and number of frozen embryos (mean 3.2 vs. 3.4).

By all measures used, pregnancy outcomes were similar between protocols, she said.

The GnRH-antagonist and GnRH-agonist groups had similar clinical pregnancy rates (35% vs. 35.7%) and clinical pregnancies per embryo transfer (42.6% vs. 41%). There were similar results for ongoing pregnancy rates analyzed per randomization (25.5% vs. 26.4%), if patient started stimulation (24.8% vs. 24.0%), and per embryo transfer (30.7% vs. 29%).

During a discussion of the results, an audience member questioned the high FSH starting doses and suggested they may be the cause of OHSS. Dr. Toftager said the trial was designed in 2007 and that they now use lower FSH doses, but that starting doses were the same in both groups.

Another attendee asked whether OHSS rates remained statistically significant after controlling for the number of oocytes collected and the gonadotropin dose, which were significantly lower in the GnRH-antagonist group and hence, so was OHSS. That analysis will likely be conducted, but the data were just received days before the presentation, Dr. Toftager said.

Merck Sharp & Dohme sponsored the study. Dr. Toftager reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Women undergoing assisted reproduction had similar pregnancy rates with gonadotropin-releasing hormone agonist and antagonist protocols, but less ovarian hyperstimulation syndrome with the GnRH-antagonist protocol in a large randomized trial.

Severe ovarian hyperstimulation syndrome (OHSS) was roughly halved with the GnRH-antagonist vs. the GnRH-agonist protocol (3.2% vs. 6.1%; P = .03), as were ascites punctures (0 vs. 2%: P = .001) and treatment changes due to risk of OHSS (5.7% vs. 10.3%; P = .006).

Patrice Wendling/Frontline Medical News

Hospital admissions for OHSS also favored the GnRH antagonist protocol (1.7% vs. 3.6%; P = .06), Dr. Mette Toftager reported at the annual meeting of the European Society of Human Reproduction and Embryology.

The exact impact of these protocols has been controversial following early reports that GnRH antagonists were associated with lower pregnancy rates.

Two 2006 meta-analyses yielded conflicting results, but were based on small heterogeneous trials that were not powered for OHSS nor pregnancy rates and were conducted in selected populations, said Dr. Toftager of Fertility Clinic, Hvidovre Hospital, Denmark.

The current noninferiority trial used few inclusion criteria – just age 18-40 years and first in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle – to prospectively enroll 1,099 women and evenly randomize them to a classic short GnRH-antagonist protocol or a classic long GnRH-agonist protocol.

Women received a fixed dose of either recombinant follicle stimulating hormone 150 IU or 225 IU based on age (≤ 36 years vs. > 36 years) and were given the option to adjust the rFSH dose based on ovarian response at stimulation day 6.

The trial was designed to detect a 2.5% difference in moderate/severe OHSS per Golan OHSS criteria between the two groups, stratified by age, IVF center, and IVF/ICSI.

At baseline, the two groups were comparable in age (mean 32 years), cycle length (mean 28.9 days), and nulliparity (92.3%). The study included women with irregular cycles and polycystic ovary syndrome, who represented about 13% of each group.

Regarding stimulation, significant differences were found between the GnRH-antagonist and GnRH-agonist groups in total rFSH dose (mean 1,522 IU vs. 1,999 IU), days of stimulation (mean 9 vs. 11), and the number of aspirated oocytes (mean 8.5 vs. 10; P < .0001 for all), Dr. Toftager reported.

The GnRH-antagonist and GnRH-agonist groups had the same number of embryos transferred (mean 1.1 vs. 1.2), use of embryo freezing (50% vs. 53%), and number of frozen embryos (mean 3.2 vs. 3.4).

By all measures used, pregnancy outcomes were similar between protocols, she said.

The GnRH-antagonist and GnRH-agonist groups had similar clinical pregnancy rates (35% vs. 35.7%) and clinical pregnancies per embryo transfer (42.6% vs. 41%). There were similar results for ongoing pregnancy rates analyzed per randomization (25.5% vs. 26.4%), if patient started stimulation (24.8% vs. 24.0%), and per embryo transfer (30.7% vs. 29%).

During a discussion of the results, an audience member questioned the high FSH starting doses and suggested they may be the cause of OHSS. Dr. Toftager said the trial was designed in 2007 and that they now use lower FSH doses, but that starting doses were the same in both groups.

Another attendee asked whether OHSS rates remained statistically significant after controlling for the number of oocytes collected and the gonadotropin dose, which were significantly lower in the GnRH-antagonist group and hence, so was OHSS. That analysis will likely be conducted, but the data were just received days before the presentation, Dr. Toftager said.

Merck Sharp & Dohme sponsored the study. Dr. Toftager reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Women undergoing assisted reproduction had similar pregnancy rates with gonadotropin-releasing hormone agonist and antagonist protocols, but less ovarian hyperstimulation syndrome with the GnRH-antagonist protocol in a large randomized trial.

Severe ovarian hyperstimulation syndrome (OHSS) was roughly halved with the GnRH-antagonist vs. the GnRH-agonist protocol (3.2% vs. 6.1%; P = .03), as were ascites punctures (0 vs. 2%: P = .001) and treatment changes due to risk of OHSS (5.7% vs. 10.3%; P = .006).

Patrice Wendling/Frontline Medical News

Hospital admissions for OHSS also favored the GnRH antagonist protocol (1.7% vs. 3.6%; P = .06), Dr. Mette Toftager reported at the annual meeting of the European Society of Human Reproduction and Embryology.

The exact impact of these protocols has been controversial following early reports that GnRH antagonists were associated with lower pregnancy rates.

Two 2006 meta-analyses yielded conflicting results, but were based on small heterogeneous trials that were not powered for OHSS nor pregnancy rates and were conducted in selected populations, said Dr. Toftager of Fertility Clinic, Hvidovre Hospital, Denmark.

The current noninferiority trial used few inclusion criteria – just age 18-40 years and first in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle – to prospectively enroll 1,099 women and evenly randomize them to a classic short GnRH-antagonist protocol or a classic long GnRH-agonist protocol.

Women received a fixed dose of either recombinant follicle stimulating hormone 150 IU or 225 IU based on age (≤ 36 years vs. > 36 years) and were given the option to adjust the rFSH dose based on ovarian response at stimulation day 6.

The trial was designed to detect a 2.5% difference in moderate/severe OHSS per Golan OHSS criteria between the two groups, stratified by age, IVF center, and IVF/ICSI.

At baseline, the two groups were comparable in age (mean 32 years), cycle length (mean 28.9 days), and nulliparity (92.3%). The study included women with irregular cycles and polycystic ovary syndrome, who represented about 13% of each group.

Regarding stimulation, significant differences were found between the GnRH-antagonist and GnRH-agonist groups in total rFSH dose (mean 1,522 IU vs. 1,999 IU), days of stimulation (mean 9 vs. 11), and the number of aspirated oocytes (mean 8.5 vs. 10; P < .0001 for all), Dr. Toftager reported.

The GnRH-antagonist and GnRH-agonist groups had the same number of embryos transferred (mean 1.1 vs. 1.2), use of embryo freezing (50% vs. 53%), and number of frozen embryos (mean 3.2 vs. 3.4).

By all measures used, pregnancy outcomes were similar between protocols, she said.

The GnRH-antagonist and GnRH-agonist groups had similar clinical pregnancy rates (35% vs. 35.7%) and clinical pregnancies per embryo transfer (42.6% vs. 41%). There were similar results for ongoing pregnancy rates analyzed per randomization (25.5% vs. 26.4%), if patient started stimulation (24.8% vs. 24.0%), and per embryo transfer (30.7% vs. 29%).

During a discussion of the results, an audience member questioned the high FSH starting doses and suggested they may be the cause of OHSS. Dr. Toftager said the trial was designed in 2007 and that they now use lower FSH doses, but that starting doses were the same in both groups.

Another attendee asked whether OHSS rates remained statistically significant after controlling for the number of oocytes collected and the gonadotropin dose, which were significantly lower in the GnRH-antagonist group and hence, so was OHSS. That analysis will likely be conducted, but the data were just received days before the presentation, Dr. Toftager said.

Merck Sharp & Dohme sponsored the study. Dr. Toftager reported having no financial conflicts.

[email protected]

On Twitter @pwendl

CHICAGO – Autologous engineered skin substitutes (EES) reduce mortality and donor-site harvesting in children with extensive, deep burns, a randomized, paired-site comparison showed.

“Autologous ESS offer an alternative therapy for closure of extensive, excised, full-thickness burns,” Steven Boyce, Ph.D., said at the annual meeting of the American Burn Association.

Patrice Wendling/Frontline Medical News

The skin substitutes were engineered using split-thickness skin biopsies from 16 children with full-thickness burns covering an average total body surface area (TBSA) of 78% and a high of 95%.

The ESS were composed of autologous cultured keratinocytes and dermal fibroblasts attached to a collagen-based, biopolymer scaffold.

Clinicians are increasingly turning to tissue engineering as a way to address the shortfalls associated with the prevailing standard of care, autologous skin grafting, including lack of donor sites in larger burns, increased morbidity from autograft harvesting and skin grafts, and scarring.

At the 2014 ABA meeting, Canadian researchers reported on an autologous skin substitute that had both dermal and epidermal components. It took 2 months to prepare, whereas the Cincinnati model requires about 1 month to prepare and offers greater availability and stability of the closed wounds, Dr. Boyce said in an interview.

For the current study, Dr. Boyce and his associates compared mortality after treatment with ESS in 16 children with data from 1,008 patients from the National Burn Repository who were of similar ages, had 77% full-thickness TBSA burns, and were treated with meshed and expanded split-thickness skin autografts (AG). One patient died before ESS were prepared, leaving 15 patients in whom 2,056 ESS grafts were applied in 59 operations. Their average age was 6.3 years, 13 were male, and the average time to first ESS was 32 days.

Mortality was 6.25% (1/16) with the skin substitutes and 30.3% (305/1,008) with the autografts (P value < .05), said Dr. Boyce, a professor with the University of Cincinnati and director of the Skin Substitute Laboratories, Shriners Hospitals for Children, both in Cincinnati.

Rates of engraftment at postoperative day 14, however, significantly favored the AG group at 96.5 vs. 83.5% for ESS (P < .05).

One major reason for reduced rates of engraftment is lack of blood vessels in current models of engineered skin, he explained.

At day 28, the percentage of TBSA closed was approximately 30% for ESS and 47% for AG, while the ratio of closed-to-donor areas was significantly greater for ESS (108.7 vs. 4.0; P < .001).

The correlation between the percentage TBSA closed with ESS and TBSA burned generated an R-squared value of 0.65 (P < .001), Dr. Boyce said.

Regraftment rates were similar between graft types. Antibody formation to the biopolymer scaffold at postoperative day 28 was similar between patients receiving 1 or multiple ESS.

“Stable wound closure [with ESS] is interpreted to result from preservation of epidermal progenitor cells, formation in vitro of basement membrane between fibroblasts and keratinocytes, and generation of fibrovascular tissue by the biopolymer scaffold,” he said.

Tissue engineering offers patients the opportunity to survive with otherwise statistically lethal burns and “the data are very clear that happens with this product,” session comoderator and past ABA president Dr. David Ahrenholz said in an interview.

That said, “the product is very expensive, so I would not use it for patients in whom I had adequate donor sites, but it’s fairly easy to identify those patients on admission,” he added.

The study was supported by grants from the U.S. Department of Defense, National Institute of General Medical Sciences, and Shriners Hospitals for Children. The authors reported no current relevant financial disclosures.

[email protected]

On Twitter @pwendl

CHICAGO – Autologous engineered skin substitutes (EES) reduce mortality and donor-site harvesting in children with extensive, deep burns, a randomized, paired-site comparison showed.

“Autologous ESS offer an alternative therapy for closure of extensive, excised, full-thickness burns,” Steven Boyce, Ph.D., said at the annual meeting of the American Burn Association.

Patrice Wendling/Frontline Medical News

The skin substitutes were engineered using split-thickness skin biopsies from 16 children with full-thickness burns covering an average total body surface area (TBSA) of 78% and a high of 95%.

The ESS were composed of autologous cultured keratinocytes and dermal fibroblasts attached to a collagen-based, biopolymer scaffold.

Clinicians are increasingly turning to tissue engineering as a way to address the shortfalls associated with the prevailing standard of care, autologous skin grafting, including lack of donor sites in larger burns, increased morbidity from autograft harvesting and skin grafts, and scarring.

At the 2014 ABA meeting, Canadian researchers reported on an autologous skin substitute that had both dermal and epidermal components. It took 2 months to prepare, whereas the Cincinnati model requires about 1 month to prepare and offers greater availability and stability of the closed wounds, Dr. Boyce said in an interview.

For the current study, Dr. Boyce and his associates compared mortality after treatment with ESS in 16 children with data from 1,008 patients from the National Burn Repository who were of similar ages, had 77% full-thickness TBSA burns, and were treated with meshed and expanded split-thickness skin autografts (AG). One patient died before ESS were prepared, leaving 15 patients in whom 2,056 ESS grafts were applied in 59 operations. Their average age was 6.3 years, 13 were male, and the average time to first ESS was 32 days.

Mortality was 6.25% (1/16) with the skin substitutes and 30.3% (305/1,008) with the autografts (P value < .05), said Dr. Boyce, a professor with the University of Cincinnati and director of the Skin Substitute Laboratories, Shriners Hospitals for Children, both in Cincinnati.

Rates of engraftment at postoperative day 14, however, significantly favored the AG group at 96.5 vs. 83.5% for ESS (P < .05).

One major reason for reduced rates of engraftment is lack of blood vessels in current models of engineered skin, he explained.

At day 28, the percentage of TBSA closed was approximately 30% for ESS and 47% for AG, while the ratio of closed-to-donor areas was significantly greater for ESS (108.7 vs. 4.0; P < .001).

The correlation between the percentage TBSA closed with ESS and TBSA burned generated an R-squared value of 0.65 (P < .001), Dr. Boyce said.

Regraftment rates were similar between graft types. Antibody formation to the biopolymer scaffold at postoperative day 28 was similar between patients receiving 1 or multiple ESS.

“Stable wound closure [with ESS] is interpreted to result from preservation of epidermal progenitor cells, formation in vitro of basement membrane between fibroblasts and keratinocytes, and generation of fibrovascular tissue by the biopolymer scaffold,” he said.

Tissue engineering offers patients the opportunity to survive with otherwise statistically lethal burns and “the data are very clear that happens with this product,” session comoderator and past ABA president Dr. David Ahrenholz said in an interview.

That said, “the product is very expensive, so I would not use it for patients in whom I had adequate donor sites, but it’s fairly easy to identify those patients on admission,” he added.

The study was supported by grants from the U.S. Department of Defense, National Institute of General Medical Sciences, and Shriners Hospitals for Children. The authors reported no current relevant financial disclosures.

[email protected]

On Twitter @pwendl

CHICAGO – Autologous engineered skin substitutes (EES) reduce mortality and donor-site harvesting in children with extensive, deep burns, a randomized, paired-site comparison showed.

“Autologous ESS offer an alternative therapy for closure of extensive, excised, full-thickness burns,” Steven Boyce, Ph.D., said at the annual meeting of the American Burn Association.

Patrice Wendling/Frontline Medical News

The skin substitutes were engineered using split-thickness skin biopsies from 16 children with full-thickness burns covering an average total body surface area (TBSA) of 78% and a high of 95%.

The ESS were composed of autologous cultured keratinocytes and dermal fibroblasts attached to a collagen-based, biopolymer scaffold.

Clinicians are increasingly turning to tissue engineering as a way to address the shortfalls associated with the prevailing standard of care, autologous skin grafting, including lack of donor sites in larger burns, increased morbidity from autograft harvesting and skin grafts, and scarring.

At the 2014 ABA meeting, Canadian researchers reported on an autologous skin substitute that had both dermal and epidermal components. It took 2 months to prepare, whereas the Cincinnati model requires about 1 month to prepare and offers greater availability and stability of the closed wounds, Dr. Boyce said in an interview.

For the current study, Dr. Boyce and his associates compared mortality after treatment with ESS in 16 children with data from 1,008 patients from the National Burn Repository who were of similar ages, had 77% full-thickness TBSA burns, and were treated with meshed and expanded split-thickness skin autografts (AG). One patient died before ESS were prepared, leaving 15 patients in whom 2,056 ESS grafts were applied in 59 operations. Their average age was 6.3 years, 13 were male, and the average time to first ESS was 32 days.

Mortality was 6.25% (1/16) with the skin substitutes and 30.3% (305/1,008) with the autografts (P value < .05), said Dr. Boyce, a professor with the University of Cincinnati and director of the Skin Substitute Laboratories, Shriners Hospitals for Children, both in Cincinnati.

Rates of engraftment at postoperative day 14, however, significantly favored the AG group at 96.5 vs. 83.5% for ESS (P < .05).

One major reason for reduced rates of engraftment is lack of blood vessels in current models of engineered skin, he explained.

At day 28, the percentage of TBSA closed was approximately 30% for ESS and 47% for AG, while the ratio of closed-to-donor areas was significantly greater for ESS (108.7 vs. 4.0; P < .001).

The correlation between the percentage TBSA closed with ESS and TBSA burned generated an R-squared value of 0.65 (P < .001), Dr. Boyce said.

Regraftment rates were similar between graft types. Antibody formation to the biopolymer scaffold at postoperative day 28 was similar between patients receiving 1 or multiple ESS.

“Stable wound closure [with ESS] is interpreted to result from preservation of epidermal progenitor cells, formation in vitro of basement membrane between fibroblasts and keratinocytes, and generation of fibrovascular tissue by the biopolymer scaffold,” he said.

Tissue engineering offers patients the opportunity to survive with otherwise statistically lethal burns and “the data are very clear that happens with this product,” session comoderator and past ABA president Dr. David Ahrenholz said in an interview.

That said, “the product is very expensive, so I would not use it for patients in whom I had adequate donor sites, but it’s fairly easy to identify those patients on admission,” he added.

The study was supported by grants from the U.S. Department of Defense, National Institute of General Medical Sciences, and Shriners Hospitals for Children. The authors reported no current relevant financial disclosures.

[email protected]

On Twitter @pwendl

WASHINGTON – More intensive treatment with early combined immunosuppression was associated with a longer time to first flare and fewer flares than conventional management during long-term follow-up of patients with Crohn’s disease.

Fewer patients treated with the “top-down” approach required anti–tumor necrosis factor (anti-TNF) agents or corticosteroids during follow-up, Dr. Daniël Hoekman reported during the annual Digestive Disease Week.

Current guidelines advocate an initial “step-up” approach for Crohn’s disease that focuses on controlling symptoms with corticosteroids followed by immunomodulators and then anti-TNF inhibitors to manage the chronic relapsing-remitting course of Crohn’s.

A new strategy has been proposed with the aim of altering the disease course and slow progression by reversing the treatment paradigm from a step-up to a top-down approach. A 2-year, randomized European trial showed that a top-down approach, combining early immunosuppression with infliximab (Remicade) and azathioprine (Imuran in Canada, Azasan in the United States) followed by azathioprine monotherapy and, if necessary, additional infliximab and corticosteroids, was more effective than step-up management for induction of remission and reduction of steroids in the short term (Lancet 2008;371:660-7).

To investigate the long-term outcome of Crohn’s disease, researchers performed a retrospective chart review in 119 of the 133 trial participants followed for 8 years or 16 semesters (mean 14.2 semesters) after the initial 2-year trial period. Management during the study was left to physician discretion. At the start of the extended follow-up, most patients in both the step-up and top-down groups were on immunomodulators (66% vs. 82%) and only a small portion were using infliximab (15% vs. 20%). A total of 164 endoscopy reports were available for 59% of patients.

During follow-up, significantly more patients treated with the step-up approach than the top-down approach required anti-TNF inhibitors (73% vs. 54%; P = .04) and steroids (62% vs. 41%; P = .02), said Dr. Hoekman of the Academic Medical Center, Amsterdam.

There was no difference between the step-up and top-down groups in long-term remission rates (70% vs. 73%; P = .85).

The top-down group, however, had significantly fewer flares than the step-up group (7% vs. 19%; P = .01) and a longer time to first flare (median 9 semesters vs. 5 semesters; P = .02), he said.

There were no differences between groups in rates of hospitalization or surgery for Crohn’s disease, new fistula, or rescue treatment, defined as use of cyclosporine, experimental therapy, or surgery.

A review of the endoscopy reports suggested a trend for fewer large ulcers per patient in the top-down group than the step-up group, but this did not reach statistical significance (14% vs. 24%; P = .11), Dr. Hoekman said. The median proportion of endoscopies with remission also was similar (49% vs. 43%; P = .46).

Rates of adverse events also were similar in the top-down and step-up groups including infusion reactions (14% vs. 10%), serious infection (22% vs. 10%), malignancy (0 vs. 1 event), and dysplastic lesions (0 vs. 2 events), he said.

[email protected]

On Twitter@pwendl

WASHINGTON – More intensive treatment with early combined immunosuppression was associated with a longer time to first flare and fewer flares than conventional management during long-term follow-up of patients with Crohn’s disease.

Fewer patients treated with the “top-down” approach required anti–tumor necrosis factor (anti-TNF) agents or corticosteroids during follow-up, Dr. Daniël Hoekman reported during the annual Digestive Disease Week.

Current guidelines advocate an initial “step-up” approach for Crohn’s disease that focuses on controlling symptoms with corticosteroids followed by immunomodulators and then anti-TNF inhibitors to manage the chronic relapsing-remitting course of Crohn’s.

A new strategy has been proposed with the aim of altering the disease course and slow progression by reversing the treatment paradigm from a step-up to a top-down approach. A 2-year, randomized European trial showed that a top-down approach, combining early immunosuppression with infliximab (Remicade) and azathioprine (Imuran in Canada, Azasan in the United States) followed by azathioprine monotherapy and, if necessary, additional infliximab and corticosteroids, was more effective than step-up management for induction of remission and reduction of steroids in the short term (Lancet 2008;371:660-7).

To investigate the long-term outcome of Crohn’s disease, researchers performed a retrospective chart review in 119 of the 133 trial participants followed for 8 years or 16 semesters (mean 14.2 semesters) after the initial 2-year trial period. Management during the study was left to physician discretion. At the start of the extended follow-up, most patients in both the step-up and top-down groups were on immunomodulators (66% vs. 82%) and only a small portion were using infliximab (15% vs. 20%). A total of 164 endoscopy reports were available for 59% of patients.

During follow-up, significantly more patients treated with the step-up approach than the top-down approach required anti-TNF inhibitors (73% vs. 54%; P = .04) and steroids (62% vs. 41%; P = .02), said Dr. Hoekman of the Academic Medical Center, Amsterdam.

There was no difference between the step-up and top-down groups in long-term remission rates (70% vs. 73%; P = .85).

The top-down group, however, had significantly fewer flares than the step-up group (7% vs. 19%; P = .01) and a longer time to first flare (median 9 semesters vs. 5 semesters; P = .02), he said.

There were no differences between groups in rates of hospitalization or surgery for Crohn’s disease, new fistula, or rescue treatment, defined as use of cyclosporine, experimental therapy, or surgery.

A review of the endoscopy reports suggested a trend for fewer large ulcers per patient in the top-down group than the step-up group, but this did not reach statistical significance (14% vs. 24%; P = .11), Dr. Hoekman said. The median proportion of endoscopies with remission also was similar (49% vs. 43%; P = .46).

Rates of adverse events also were similar in the top-down and step-up groups including infusion reactions (14% vs. 10%), serious infection (22% vs. 10%), malignancy (0 vs. 1 event), and dysplastic lesions (0 vs. 2 events), he said.

[email protected]

On Twitter@pwendl

WASHINGTON – More intensive treatment with early combined immunosuppression was associated with a longer time to first flare and fewer flares than conventional management during long-term follow-up of patients with Crohn’s disease.

Fewer patients treated with the “top-down” approach required anti–tumor necrosis factor (anti-TNF) agents or corticosteroids during follow-up, Dr. Daniël Hoekman reported during the annual Digestive Disease Week.

Current guidelines advocate an initial “step-up” approach for Crohn’s disease that focuses on controlling symptoms with corticosteroids followed by immunomodulators and then anti-TNF inhibitors to manage the chronic relapsing-remitting course of Crohn’s.

A new strategy has been proposed with the aim of altering the disease course and slow progression by reversing the treatment paradigm from a step-up to a top-down approach. A 2-year, randomized European trial showed that a top-down approach, combining early immunosuppression with infliximab (Remicade) and azathioprine (Imuran in Canada, Azasan in the United States) followed by azathioprine monotherapy and, if necessary, additional infliximab and corticosteroids, was more effective than step-up management for induction of remission and reduction of steroids in the short term (Lancet 2008;371:660-7).

To investigate the long-term outcome of Crohn’s disease, researchers performed a retrospective chart review in 119 of the 133 trial participants followed for 8 years or 16 semesters (mean 14.2 semesters) after the initial 2-year trial period. Management during the study was left to physician discretion. At the start of the extended follow-up, most patients in both the step-up and top-down groups were on immunomodulators (66% vs. 82%) and only a small portion were using infliximab (15% vs. 20%). A total of 164 endoscopy reports were available for 59% of patients.

During follow-up, significantly more patients treated with the step-up approach than the top-down approach required anti-TNF inhibitors (73% vs. 54%; P = .04) and steroids (62% vs. 41%; P = .02), said Dr. Hoekman of the Academic Medical Center, Amsterdam.

There was no difference between the step-up and top-down groups in long-term remission rates (70% vs. 73%; P = .85).

The top-down group, however, had significantly fewer flares than the step-up group (7% vs. 19%; P = .01) and a longer time to first flare (median 9 semesters vs. 5 semesters; P = .02), he said.

There were no differences between groups in rates of hospitalization or surgery for Crohn’s disease, new fistula, or rescue treatment, defined as use of cyclosporine, experimental therapy, or surgery.

A review of the endoscopy reports suggested a trend for fewer large ulcers per patient in the top-down group than the step-up group, but this did not reach statistical significance (14% vs. 24%; P = .11), Dr. Hoekman said. The median proportion of endoscopies with remission also was similar (49% vs. 43%; P = .46).

Rates of adverse events also were similar in the top-down and step-up groups including infusion reactions (14% vs. 10%), serious infection (22% vs. 10%), malignancy (0 vs. 1 event), and dysplastic lesions (0 vs. 2 events), he said.

[email protected]

On Twitter@pwendl

WASHINGTON – A simple dietary challenge may help identify nonceliac gluten sensitivity in patients with gastrointestinal functional disorders, results of the ongoing, randomized GLUTOX trial suggest.

Nonceliac gluten sensitivity is an emergent syndrome that causes mainly gastrointestinal symptoms and has been thought to be present in about 6% of the population. The problem is that there is no established or well-defined diagnostic flow chart to identify these patients, study author Dr. Luca Elli said at the annual Digestive Disease Week.

To determine whether gluten induces symptoms in patients responding positively to a gluten-free diet and identify those potentially affected by nonceliac gluten sensitivity, GLUTOX enrolled 100 adults with functional GI symptoms and placed them on a gluten-free diet for 21 days. Severity of symptoms was measured before and after the diet using a 10-cm visual analogue scale (VAS) and the 36-item Short Form Health Survey (SF-36).

Patients with at least a 3-cm improvement in baseline VAS were then double-blind, randomly assigned to gluten (5.6 g per day) or placebo capsules for 7 days, followed by a 7-day washout period, and then crossed over to another 7-day cycle of gluten or placebo capsules.

Patrice Wendling/Frontline Medical News

At baseline, the mean age was 38 years, 90% of patients were female, 55 had irritable bowel syndrome, 36 functional dyspepsia, and 9 had other unspecified functional nonspecific gastrointestinal symptoms by ROME III criteria.

Patients with celiac disease or a wheat allergy or who were on an ongoing gluten-free diet were excluded.

In all, 81 patients reported a symptomatic improvement from baseline after the 21-day gluten-free-diet (mean VAS 7.5 vs. 3.3; P value = .001), Dr. Elli, from Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan reported in a distinguished abstract plenary session.

“All of the symptoms we found were reduced by the gluten-free diet, but especially patient satisfaction about stool consistency, bloating, and the global satisfaction were improved in an important way,” he said.

Symptom improvements were also associated with significant improvements in the SF-36 physical component summary and mental component summary. Most responders were female (88%); 48 had irritable bowel syndrome, 25 dyspepsia, and 8 other.

After the gluten capsule challenge, 25 of the 81 gluten-free diet responders had a severe symptomatic relapse especially in stool consistency satisfaction, bloating, and abdominal pain, Dr. Elli said.

The relapses were also associated with a significant decrease in SF-36 physical and mental component summaries.

No demographic or biochemical parameters were significantly associated with a response to the gluten challenge, Dr. Elli said. Most of those having a response were female (96%); 13 had irritable bowel syndrome, 10 dyspepsia, and 2 other.

The sequence of the gluten and placebo capsules also had no effect on the results.

If the data are confirmed, it’s possible the double-blind challenge could be used to select gluten-free diet responders and inserted into the diagnostic flow chart for patients with gastrointestinal functional disorders, Dr. Elli said.

A very important open issue is also the 56% of enrolled subjects who responded to the gluten-free diet, but did not show symptoms with the gluten double-blind challenge, he added.

During a discussion of the results, attendees questioned whether the study design, particularly the failure to biopsy patients for celiac disease at enrollment and the short 7-day washout period, was sufficient to answer the question of identifying patients with nonceliac gluten sensitivity.

Session comoderator Dr. Bernd Schnabl, from University of California–San Diego, agreed that the study design was not ideal and that the study would have been strengthened by using biopsy to rule out patients with celiac disease. That said, the study represents a start.

“If we can stratify these patients and re-challenge them longer, it could be helpful in identifying a subpopulation of functional patients who might benefit from a gluten-free diet,” he said.

[email protected]

On Twitter @pwendl

WASHINGTON – A simple dietary challenge may help identify nonceliac gluten sensitivity in patients with gastrointestinal functional disorders, results of the ongoing, randomized GLUTOX trial suggest.

Nonceliac gluten sensitivity is an emergent syndrome that causes mainly gastrointestinal symptoms and has been thought to be present in about 6% of the population. The problem is that there is no established or well-defined diagnostic flow chart to identify these patients, study author Dr. Luca Elli said at the annual Digestive Disease Week.

To determine whether gluten induces symptoms in patients responding positively to a gluten-free diet and identify those potentially affected by nonceliac gluten sensitivity, GLUTOX enrolled 100 adults with functional GI symptoms and placed them on a gluten-free diet for 21 days. Severity of symptoms was measured before and after the diet using a 10-cm visual analogue scale (VAS) and the 36-item Short Form Health Survey (SF-36).

Patients with at least a 3-cm improvement in baseline VAS were then double-blind, randomly assigned to gluten (5.6 g per day) or placebo capsules for 7 days, followed by a 7-day washout period, and then crossed over to another 7-day cycle of gluten or placebo capsules.

Patrice Wendling/Frontline Medical News

At baseline, the mean age was 38 years, 90% of patients were female, 55 had irritable bowel syndrome, 36 functional dyspepsia, and 9 had other unspecified functional nonspecific gastrointestinal symptoms by ROME III criteria.

Patients with celiac disease or a wheat allergy or who were on an ongoing gluten-free diet were excluded.

In all, 81 patients reported a symptomatic improvement from baseline after the 21-day gluten-free-diet (mean VAS 7.5 vs. 3.3; P value = .001), Dr. Elli, from Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan reported in a distinguished abstract plenary session.

“All of the symptoms we found were reduced by the gluten-free diet, but especially patient satisfaction about stool consistency, bloating, and the global satisfaction were improved in an important way,” he said.

Symptom improvements were also associated with significant improvements in the SF-36 physical component summary and mental component summary. Most responders were female (88%); 48 had irritable bowel syndrome, 25 dyspepsia, and 8 other.

After the gluten capsule challenge, 25 of the 81 gluten-free diet responders had a severe symptomatic relapse especially in stool consistency satisfaction, bloating, and abdominal pain, Dr. Elli said.

The relapses were also associated with a significant decrease in SF-36 physical and mental component summaries.

No demographic or biochemical parameters were significantly associated with a response to the gluten challenge, Dr. Elli said. Most of those having a response were female (96%); 13 had irritable bowel syndrome, 10 dyspepsia, and 2 other.

The sequence of the gluten and placebo capsules also had no effect on the results.

If the data are confirmed, it’s possible the double-blind challenge could be used to select gluten-free diet responders and inserted into the diagnostic flow chart for patients with gastrointestinal functional disorders, Dr. Elli said.

A very important open issue is also the 56% of enrolled subjects who responded to the gluten-free diet, but did not show symptoms with the gluten double-blind challenge, he added.

During a discussion of the results, attendees questioned whether the study design, particularly the failure to biopsy patients for celiac disease at enrollment and the short 7-day washout period, was sufficient to answer the question of identifying patients with nonceliac gluten sensitivity.

Session comoderator Dr. Bernd Schnabl, from University of California–San Diego, agreed that the study design was not ideal and that the study would have been strengthened by using biopsy to rule out patients with celiac disease. That said, the study represents a start.

“If we can stratify these patients and re-challenge them longer, it could be helpful in identifying a subpopulation of functional patients who might benefit from a gluten-free diet,” he said.

[email protected]

On Twitter @pwendl

WASHINGTON – A simple dietary challenge may help identify nonceliac gluten sensitivity in patients with gastrointestinal functional disorders, results of the ongoing, randomized GLUTOX trial suggest.

Nonceliac gluten sensitivity is an emergent syndrome that causes mainly gastrointestinal symptoms and has been thought to be present in about 6% of the population. The problem is that there is no established or well-defined diagnostic flow chart to identify these patients, study author Dr. Luca Elli said at the annual Digestive Disease Week.

To determine whether gluten induces symptoms in patients responding positively to a gluten-free diet and identify those potentially affected by nonceliac gluten sensitivity, GLUTOX enrolled 100 adults with functional GI symptoms and placed them on a gluten-free diet for 21 days. Severity of symptoms was measured before and after the diet using a 10-cm visual analogue scale (VAS) and the 36-item Short Form Health Survey (SF-36).

Patients with at least a 3-cm improvement in baseline VAS were then double-blind, randomly assigned to gluten (5.6 g per day) or placebo capsules for 7 days, followed by a 7-day washout period, and then crossed over to another 7-day cycle of gluten or placebo capsules.

Patrice Wendling/Frontline Medical News

At baseline, the mean age was 38 years, 90% of patients were female, 55 had irritable bowel syndrome, 36 functional dyspepsia, and 9 had other unspecified functional nonspecific gastrointestinal symptoms by ROME III criteria.

Patients with celiac disease or a wheat allergy or who were on an ongoing gluten-free diet were excluded.

In all, 81 patients reported a symptomatic improvement from baseline after the 21-day gluten-free-diet (mean VAS 7.5 vs. 3.3; P value = .001), Dr. Elli, from Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan reported in a distinguished abstract plenary session.

“All of the symptoms we found were reduced by the gluten-free diet, but especially patient satisfaction about stool consistency, bloating, and the global satisfaction were improved in an important way,” he said.

Symptom improvements were also associated with significant improvements in the SF-36 physical component summary and mental component summary. Most responders were female (88%); 48 had irritable bowel syndrome, 25 dyspepsia, and 8 other.

After the gluten capsule challenge, 25 of the 81 gluten-free diet responders had a severe symptomatic relapse especially in stool consistency satisfaction, bloating, and abdominal pain, Dr. Elli said.

The relapses were also associated with a significant decrease in SF-36 physical and mental component summaries.

No demographic or biochemical parameters were significantly associated with a response to the gluten challenge, Dr. Elli said. Most of those having a response were female (96%); 13 had irritable bowel syndrome, 10 dyspepsia, and 2 other.

The sequence of the gluten and placebo capsules also had no effect on the results.

If the data are confirmed, it’s possible the double-blind challenge could be used to select gluten-free diet responders and inserted into the diagnostic flow chart for patients with gastrointestinal functional disorders, Dr. Elli said.

A very important open issue is also the 56% of enrolled subjects who responded to the gluten-free diet, but did not show symptoms with the gluten double-blind challenge, he added.

During a discussion of the results, attendees questioned whether the study design, particularly the failure to biopsy patients for celiac disease at enrollment and the short 7-day washout period, was sufficient to answer the question of identifying patients with nonceliac gluten sensitivity.

Session comoderator Dr. Bernd Schnabl, from University of California–San Diego, agreed that the study design was not ideal and that the study would have been strengthened by using biopsy to rule out patients with celiac disease. That said, the study represents a start.

“If we can stratify these patients and re-challenge them longer, it could be helpful in identifying a subpopulation of functional patients who might benefit from a gluten-free diet,” he said.

[email protected]

On Twitter @pwendl

VIENNA – The investigational P13K-delta inhibitor TGR-1202 was clinically active in relapsed or refractory chronic lymphocytic leukemia and other hematologic malignancies in an ongoing phase I trial.

TGR-1202 is entering an increasingly crowded field of P13 kinase inhibitors including idelalisib (Zydelig) and duvelisib, but a more benign safety profile may separate it from the pack.

“It has a different AE [adverse event] profile, compared with some of the other agents, with a little less on the hepatotoxicity side and, at least to date, we actually haven’t seen any evidence of colitis,” Dr. Owen O’Connor said at the annual congress of the European Hematology Association.

Citing recently reported data, grade 3/4 diarrhea/colitis occurs in 10%-22% of patients treated with idelalisib, idelalisib plus ofatumumab, or duvelisib versus just 1% of all 137 patients treated in TGR-1202 studies to date, he noted.

TGR-1202 also has less grade 3/4 pneumonia (4%) and elevated liver enzymes (2%), compared with rates of 13%-16% and 13%-17%, respectively, for the other P13K therapies.

Further, just 4% of all patients have discontinued TGR-1202 because of adverse events vs. 12% on idelalisib, 31% on idelalisib plus ofatumumab, and 33% on duvelisib.

“I think this may bode well as we think about how to combine P13 kinase inhibitors into other regimens to try to look at various combination regimens,” said Dr. O’Connor, director of the Center for Lymphoid Malignancies at Columbia University in New York.

Courtesy Columbia University Medical Center

He presented data on 66 patients with relapsed or refractory B- or T-cell malignancies including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia and Hodgkin lymphoma. More than half (55%) had received at least three prior therapies (range 1-14) and 52% were refractory to the most recent regimen.

The dose-escalation study evaluated TGR-1202 once-daily at doses of 50 mg to 1,800 mg and a micronized formulation dosed at 200 mg to 1,800 mg.

The most common adverse event of any grade was nausea (41%), diarrhea and fatigue (32% each), headache and vomiting (23% each), and cough (21%), Dr. O’Connor said. Grade 3 or 4 adverse events were neutropenia (11%), anemia (8%), hypokalemia and dyspnea (5% each), and diarrhea and constipation (2% each).

A strong dose-response relationship was observed among 51 patients evaluable for efficacy, with higher doses of TGR-1202 (1,200-mg initial formulation or ≥ 600 mg micronized) demonstrating rapid and profound responses, he said.

In the CLL subgroup, 14 of 16 patients (88%) achieved a nodal partial response and 10 (63%) achieved a response per International Workshop on CLL (iwCLL) criteria.

Of the 12 evaluable patients with follicular lymphoma, 5 achieved a partial response (nodal reduction > 50%), with 3 of the 6 patients treated at higher doses reaching a partial response.

A heavily pretreated patient with Hodgkin lymphoma also achieved a near-complete response, Dr. O’Connor said.

At the time of the analysis, 37 of 66 patients had received micronized TGR-1202 at doses ≥ 800 mg. Of these, 25 remain on study and have reached a median progression-free survival of 9.5 months.

Expansion cohorts are enrolling at 800 mg and 1,200 mg of the micronized formulation, and are the targeted doses for phase II studies in development, he said.

Duvelisib

In a separate presentation during the same session, phase I results showed twice-daily duvelisib 25 mg resulted in an overall response rate of 88%, including 15 partial responses in 17 evaluable patients with treatment-naive CLL.

All but one of nine patients with a deleterious P53 mutation or 17p deletion achieved a partial response, Dr. Susan O’Brien of University of California, Irvine, reported.

“The advantage of duvelisib is that responses are more rapid than with other single agent B-cell receptors,” she said in an interview.

The median time to iwCLL response was 3.7 months, with 7 of the 15 responses occurring by the first assessment (cycle 3, day 1).

Pharmacodynamic and mechanism of action studies show duvelisib, an oral P13K-delta/gamma inhibitor, produces rapid inhibition of phosphorylation of AKT (pAKT) sustained through cycle 2, day 1 and near-complete inhibition of CLL proliferation (Ki67) following 1 cycle of duvelisib.

Key serum chemokines and cytokines known to contribute to CLL growth and survival also decreased following duvelisib, suggesting modulation of the tumor microenvironment, Dr. O’Brien said.

Of the 18 patients treated in the CLL expansion cohort, 10 remain on treatment and 8 discontinued treatment, including 6 patients who discontinued treatment because of adverse events. The median time on treatment was 14 months (range 1-20 months). Adverse events were mostly grade 1 or 2, reversible, and clinically manageable, she said.

The most common grade 3 adverse events were diarrhea (22%) and liver enzyme elevations (17%), with grade 4 neutropenia occurring in 28%.

In 16 patients with baseline computed tomography assessments, 88% achieved a nodal response (≥ 50% reduction in measurable area of disease) and all had a PR per iwCLL.

Median progression-free and overall survival had not been reached, with a 92% PFS rate and 94% survival rate at 18 months, Dr. O’Brien said. One patient died during follow-up, about 5 months after the last duvelisib dose.

Based on the pharmacodynamic/pharmacokinetic profile and clinical activity, the 25-mg twice-daily dose has been selected for phase III evaluation, she said.

[email protected]

On Twitter@pwendl

VIENNA – The investigational P13K-delta inhibitor TGR-1202 was clinically active in relapsed or refractory chronic lymphocytic leukemia and other hematologic malignancies in an ongoing phase I trial.

TGR-1202 is entering an increasingly crowded field of P13 kinase inhibitors including idelalisib (Zydelig) and duvelisib, but a more benign safety profile may separate it from the pack.

“It has a different AE [adverse event] profile, compared with some of the other agents, with a little less on the hepatotoxicity side and, at least to date, we actually haven’t seen any evidence of colitis,” Dr. Owen O’Connor said at the annual congress of the European Hematology Association.

Citing recently reported data, grade 3/4 diarrhea/colitis occurs in 10%-22% of patients treated with idelalisib, idelalisib plus ofatumumab, or duvelisib versus just 1% of all 137 patients treated in TGR-1202 studies to date, he noted.

TGR-1202 also has less grade 3/4 pneumonia (4%) and elevated liver enzymes (2%), compared with rates of 13%-16% and 13%-17%, respectively, for the other P13K therapies.

Further, just 4% of all patients have discontinued TGR-1202 because of adverse events vs. 12% on idelalisib, 31% on idelalisib plus ofatumumab, and 33% on duvelisib.

“I think this may bode well as we think about how to combine P13 kinase inhibitors into other regimens to try to look at various combination regimens,” said Dr. O’Connor, director of the Center for Lymphoid Malignancies at Columbia University in New York.

Courtesy Columbia University Medical Center

He presented data on 66 patients with relapsed or refractory B- or T-cell malignancies including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia and Hodgkin lymphoma. More than half (55%) had received at least three prior therapies (range 1-14) and 52% were refractory to the most recent regimen.

The dose-escalation study evaluated TGR-1202 once-daily at doses of 50 mg to 1,800 mg and a micronized formulation dosed at 200 mg to 1,800 mg.

The most common adverse event of any grade was nausea (41%), diarrhea and fatigue (32% each), headache and vomiting (23% each), and cough (21%), Dr. O’Connor said. Grade 3 or 4 adverse events were neutropenia (11%), anemia (8%), hypokalemia and dyspnea (5% each), and diarrhea and constipation (2% each).

A strong dose-response relationship was observed among 51 patients evaluable for efficacy, with higher doses of TGR-1202 (1,200-mg initial formulation or ≥ 600 mg micronized) demonstrating rapid and profound responses, he said.

In the CLL subgroup, 14 of 16 patients (88%) achieved a nodal partial response and 10 (63%) achieved a response per International Workshop on CLL (iwCLL) criteria.

Of the 12 evaluable patients with follicular lymphoma, 5 achieved a partial response (nodal reduction > 50%), with 3 of the 6 patients treated at higher doses reaching a partial response.

A heavily pretreated patient with Hodgkin lymphoma also achieved a near-complete response, Dr. O’Connor said.

At the time of the analysis, 37 of 66 patients had received micronized TGR-1202 at doses ≥ 800 mg. Of these, 25 remain on study and have reached a median progression-free survival of 9.5 months.

Expansion cohorts are enrolling at 800 mg and 1,200 mg of the micronized formulation, and are the targeted doses for phase II studies in development, he said.

Duvelisib

In a separate presentation during the same session, phase I results showed twice-daily duvelisib 25 mg resulted in an overall response rate of 88%, including 15 partial responses in 17 evaluable patients with treatment-naive CLL.

All but one of nine patients with a deleterious P53 mutation or 17p deletion achieved a partial response, Dr. Susan O’Brien of University of California, Irvine, reported.

“The advantage of duvelisib is that responses are more rapid than with other single agent B-cell receptors,” she said in an interview.

The median time to iwCLL response was 3.7 months, with 7 of the 15 responses occurring by the first assessment (cycle 3, day 1).

Pharmacodynamic and mechanism of action studies show duvelisib, an oral P13K-delta/gamma inhibitor, produces rapid inhibition of phosphorylation of AKT (pAKT) sustained through cycle 2, day 1 and near-complete inhibition of CLL proliferation (Ki67) following 1 cycle of duvelisib.

Key serum chemokines and cytokines known to contribute to CLL growth and survival also decreased following duvelisib, suggesting modulation of the tumor microenvironment, Dr. O’Brien said.

Of the 18 patients treated in the CLL expansion cohort, 10 remain on treatment and 8 discontinued treatment, including 6 patients who discontinued treatment because of adverse events. The median time on treatment was 14 months (range 1-20 months). Adverse events were mostly grade 1 or 2, reversible, and clinically manageable, she said.

The most common grade 3 adverse events were diarrhea (22%) and liver enzyme elevations (17%), with grade 4 neutropenia occurring in 28%.

In 16 patients with baseline computed tomography assessments, 88% achieved a nodal response (≥ 50% reduction in measurable area of disease) and all had a PR per iwCLL.

Median progression-free and overall survival had not been reached, with a 92% PFS rate and 94% survival rate at 18 months, Dr. O’Brien said. One patient died during follow-up, about 5 months after the last duvelisib dose.

Based on the pharmacodynamic/pharmacokinetic profile and clinical activity, the 25-mg twice-daily dose has been selected for phase III evaluation, she said.

[email protected]

On Twitter@pwendl

VIENNA – The investigational P13K-delta inhibitor TGR-1202 was clinically active in relapsed or refractory chronic lymphocytic leukemia and other hematologic malignancies in an ongoing phase I trial.

TGR-1202 is entering an increasingly crowded field of P13 kinase inhibitors including idelalisib (Zydelig) and duvelisib, but a more benign safety profile may separate it from the pack.

“It has a different AE [adverse event] profile, compared with some of the other agents, with a little less on the hepatotoxicity side and, at least to date, we actually haven’t seen any evidence of colitis,” Dr. Owen O’Connor said at the annual congress of the European Hematology Association.

Citing recently reported data, grade 3/4 diarrhea/colitis occurs in 10%-22% of patients treated with idelalisib, idelalisib plus ofatumumab, or duvelisib versus just 1% of all 137 patients treated in TGR-1202 studies to date, he noted.

TGR-1202 also has less grade 3/4 pneumonia (4%) and elevated liver enzymes (2%), compared with rates of 13%-16% and 13%-17%, respectively, for the other P13K therapies.

Further, just 4% of all patients have discontinued TGR-1202 because of adverse events vs. 12% on idelalisib, 31% on idelalisib plus ofatumumab, and 33% on duvelisib.

“I think this may bode well as we think about how to combine P13 kinase inhibitors into other regimens to try to look at various combination regimens,” said Dr. O’Connor, director of the Center for Lymphoid Malignancies at Columbia University in New York.

Courtesy Columbia University Medical Center

He presented data on 66 patients with relapsed or refractory B- or T-cell malignancies including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia and Hodgkin lymphoma. More than half (55%) had received at least three prior therapies (range 1-14) and 52% were refractory to the most recent regimen.

The dose-escalation study evaluated TGR-1202 once-daily at doses of 50 mg to 1,800 mg and a micronized formulation dosed at 200 mg to 1,800 mg.

The most common adverse event of any grade was nausea (41%), diarrhea and fatigue (32% each), headache and vomiting (23% each), and cough (21%), Dr. O’Connor said. Grade 3 or 4 adverse events were neutropenia (11%), anemia (8%), hypokalemia and dyspnea (5% each), and diarrhea and constipation (2% each).

A strong dose-response relationship was observed among 51 patients evaluable for efficacy, with higher doses of TGR-1202 (1,200-mg initial formulation or ≥ 600 mg micronized) demonstrating rapid and profound responses, he said.

In the CLL subgroup, 14 of 16 patients (88%) achieved a nodal partial response and 10 (63%) achieved a response per International Workshop on CLL (iwCLL) criteria.

Of the 12 evaluable patients with follicular lymphoma, 5 achieved a partial response (nodal reduction > 50%), with 3 of the 6 patients treated at higher doses reaching a partial response.

A heavily pretreated patient with Hodgkin lymphoma also achieved a near-complete response, Dr. O’Connor said.

At the time of the analysis, 37 of 66 patients had received micronized TGR-1202 at doses ≥ 800 mg. Of these, 25 remain on study and have reached a median progression-free survival of 9.5 months.

Expansion cohorts are enrolling at 800 mg and 1,200 mg of the micronized formulation, and are the targeted doses for phase II studies in development, he said.

Duvelisib

In a separate presentation during the same session, phase I results showed twice-daily duvelisib 25 mg resulted in an overall response rate of 88%, including 15 partial responses in 17 evaluable patients with treatment-naive CLL.

All but one of nine patients with a deleterious P53 mutation or 17p deletion achieved a partial response, Dr. Susan O’Brien of University of California, Irvine, reported.

“The advantage of duvelisib is that responses are more rapid than with other single agent B-cell receptors,” she said in an interview.

The median time to iwCLL response was 3.7 months, with 7 of the 15 responses occurring by the first assessment (cycle 3, day 1).

Pharmacodynamic and mechanism of action studies show duvelisib, an oral P13K-delta/gamma inhibitor, produces rapid inhibition of phosphorylation of AKT (pAKT) sustained through cycle 2, day 1 and near-complete inhibition of CLL proliferation (Ki67) following 1 cycle of duvelisib.

Key serum chemokines and cytokines known to contribute to CLL growth and survival also decreased following duvelisib, suggesting modulation of the tumor microenvironment, Dr. O’Brien said.

Of the 18 patients treated in the CLL expansion cohort, 10 remain on treatment and 8 discontinued treatment, including 6 patients who discontinued treatment because of adverse events. The median time on treatment was 14 months (range 1-20 months). Adverse events were mostly grade 1 or 2, reversible, and clinically manageable, she said.

The most common grade 3 adverse events were diarrhea (22%) and liver enzyme elevations (17%), with grade 4 neutropenia occurring in 28%.

In 16 patients with baseline computed tomography assessments, 88% achieved a nodal response (≥ 50% reduction in measurable area of disease) and all had a PR per iwCLL.

Median progression-free and overall survival had not been reached, with a 92% PFS rate and 94% survival rate at 18 months, Dr. O’Brien said. One patient died during follow-up, about 5 months after the last duvelisib dose.

Based on the pharmacodynamic/pharmacokinetic profile and clinical activity, the 25-mg twice-daily dose has been selected for phase III evaluation, she said.

[email protected]

On Twitter@pwendl