Patrice Wendling

WASHINGTON– The oral S1P receptor modulator ozanimod is clinically active and well tolerated in patients with moderate to severe ulcerative colitis (UC), phase II study results show.

Importantly, no notable cardiac, opthalmologic, or infectious treatment-related adverse events were observed, Dr. William Sandborn said at the annual Digestive Disease Week.

The first sphingosine-1-phosphate (S1P) receptor modulator, Fingolimod (Gilenya), carries a warning for first-dose cardiac effects, liver function test elevations, and macular edema and targets S1P receptors 1, 3, 4, and 5. Ozanimod is a next-generation S1P receptor modulator that has increased selectivity for the S1P receptors 1 and 5, compared with receptor 3, which may be related to safety concerns with fingolimod, said Dr. Sandborn, chief of gastroenterology at the University of California-San Diego.

He reported on the double-blind, phase II TOUCHSTONE trial involving 197 adults with moderate to severe UC who were receiving oral aminosalicylates and/or prednisone, and were randomly assigned to receive ozanimod 0.5 mg (n = 65) or 1 mg (n = 67) or placebo (n = 65). Doses were titrated through week 1, followed by 8 weeks of full-dose therapy.

The study’s primary efficacy endpoint was the proportion of patients in clinical remission at week 8, defined as a Mayo score of 2 or less, with no subscore of more than 1.

At week 8, 16.4% of patients on ozanimod 1 mg were in remission vs. 6.2% on placebo (P = .0482) and 13.8% on ozanimod 0.5 mg (P = .1422), Dr. Sandborn reported.

Rates of clinical response at 8 weeks were 56.7% with the high-dose ozanimod, 53.8% with the low dose, and 37% with placebo. Once again, the between-group difference was significant only for high-dose ozanimod (P = .0207).

Mucosal improvement was significantly more common with either high-dose ozanimod (34.3% vs. 12.3% placebo; P = .0023) or low-dose ozanimod (27.7% vs. 12.3% placebo; P = .0348), he said.

The most common adverse events were anemia/decreased hemoglobin, occurring in four patients in the placebo and low-dose ozanimod groups, and worsening of UC, occurring in three patients on placebo, two on low-dose ozanimod, and one on high-dose ozanimod.

Serious treatment-related adverse events were reported in four patients on placebo, one on ozanimod 0.5 mg (hyperpyrexia), and one on ozanimod 1 mg (UC).

The overall incidence of cardiac events was low, with two palpitations reported in the placebo group, one sinus bradycardia and one first-degree AV block in the ozanimod 0.5-mg group, and none in the 1-mg group.

“Ozanimod was well tolerated with a favorable benefit-risk profile supporting the planned phase III trial in ulcerative colitis and the phase II study in Crohn’s disease,” said Dr. Sandborn, who also reported the results earlier this year in Europe.

[email protected]

On Twitter@pwendl

WASHINGTON– The oral S1P receptor modulator ozanimod is clinically active and well tolerated in patients with moderate to severe ulcerative colitis (UC), phase II study results show.

Importantly, no notable cardiac, opthalmologic, or infectious treatment-related adverse events were observed, Dr. William Sandborn said at the annual Digestive Disease Week.

The first sphingosine-1-phosphate (S1P) receptor modulator, Fingolimod (Gilenya), carries a warning for first-dose cardiac effects, liver function test elevations, and macular edema and targets S1P receptors 1, 3, 4, and 5. Ozanimod is a next-generation S1P receptor modulator that has increased selectivity for the S1P receptors 1 and 5, compared with receptor 3, which may be related to safety concerns with fingolimod, said Dr. Sandborn, chief of gastroenterology at the University of California-San Diego.

He reported on the double-blind, phase II TOUCHSTONE trial involving 197 adults with moderate to severe UC who were receiving oral aminosalicylates and/or prednisone, and were randomly assigned to receive ozanimod 0.5 mg (n = 65) or 1 mg (n = 67) or placebo (n = 65). Doses were titrated through week 1, followed by 8 weeks of full-dose therapy.

The study’s primary efficacy endpoint was the proportion of patients in clinical remission at week 8, defined as a Mayo score of 2 or less, with no subscore of more than 1.

At week 8, 16.4% of patients on ozanimod 1 mg were in remission vs. 6.2% on placebo (P = .0482) and 13.8% on ozanimod 0.5 mg (P = .1422), Dr. Sandborn reported.

Rates of clinical response at 8 weeks were 56.7% with the high-dose ozanimod, 53.8% with the low dose, and 37% with placebo. Once again, the between-group difference was significant only for high-dose ozanimod (P = .0207).

Mucosal improvement was significantly more common with either high-dose ozanimod (34.3% vs. 12.3% placebo; P = .0023) or low-dose ozanimod (27.7% vs. 12.3% placebo; P = .0348), he said.

The most common adverse events were anemia/decreased hemoglobin, occurring in four patients in the placebo and low-dose ozanimod groups, and worsening of UC, occurring in three patients on placebo, two on low-dose ozanimod, and one on high-dose ozanimod.

Serious treatment-related adverse events were reported in four patients on placebo, one on ozanimod 0.5 mg (hyperpyrexia), and one on ozanimod 1 mg (UC).

The overall incidence of cardiac events was low, with two palpitations reported in the placebo group, one sinus bradycardia and one first-degree AV block in the ozanimod 0.5-mg group, and none in the 1-mg group.

“Ozanimod was well tolerated with a favorable benefit-risk profile supporting the planned phase III trial in ulcerative colitis and the phase II study in Crohn’s disease,” said Dr. Sandborn, who also reported the results earlier this year in Europe.

[email protected]

On Twitter@pwendl

WASHINGTON– The oral S1P receptor modulator ozanimod is clinically active and well tolerated in patients with moderate to severe ulcerative colitis (UC), phase II study results show.

Importantly, no notable cardiac, opthalmologic, or infectious treatment-related adverse events were observed, Dr. William Sandborn said at the annual Digestive Disease Week.

The first sphingosine-1-phosphate (S1P) receptor modulator, Fingolimod (Gilenya), carries a warning for first-dose cardiac effects, liver function test elevations, and macular edema and targets S1P receptors 1, 3, 4, and 5. Ozanimod is a next-generation S1P receptor modulator that has increased selectivity for the S1P receptors 1 and 5, compared with receptor 3, which may be related to safety concerns with fingolimod, said Dr. Sandborn, chief of gastroenterology at the University of California-San Diego.

He reported on the double-blind, phase II TOUCHSTONE trial involving 197 adults with moderate to severe UC who were receiving oral aminosalicylates and/or prednisone, and were randomly assigned to receive ozanimod 0.5 mg (n = 65) or 1 mg (n = 67) or placebo (n = 65). Doses were titrated through week 1, followed by 8 weeks of full-dose therapy.

The study’s primary efficacy endpoint was the proportion of patients in clinical remission at week 8, defined as a Mayo score of 2 or less, with no subscore of more than 1.

At week 8, 16.4% of patients on ozanimod 1 mg were in remission vs. 6.2% on placebo (P = .0482) and 13.8% on ozanimod 0.5 mg (P = .1422), Dr. Sandborn reported.

Rates of clinical response at 8 weeks were 56.7% with the high-dose ozanimod, 53.8% with the low dose, and 37% with placebo. Once again, the between-group difference was significant only for high-dose ozanimod (P = .0207).

Mucosal improvement was significantly more common with either high-dose ozanimod (34.3% vs. 12.3% placebo; P = .0023) or low-dose ozanimod (27.7% vs. 12.3% placebo; P = .0348), he said.

The most common adverse events were anemia/decreased hemoglobin, occurring in four patients in the placebo and low-dose ozanimod groups, and worsening of UC, occurring in three patients on placebo, two on low-dose ozanimod, and one on high-dose ozanimod.

Serious treatment-related adverse events were reported in four patients on placebo, one on ozanimod 0.5 mg (hyperpyrexia), and one on ozanimod 1 mg (UC).

The overall incidence of cardiac events was low, with two palpitations reported in the placebo group, one sinus bradycardia and one first-degree AV block in the ozanimod 0.5-mg group, and none in the 1-mg group.

“Ozanimod was well tolerated with a favorable benefit-risk profile supporting the planned phase III trial in ulcerative colitis and the phase II study in Crohn’s disease,” said Dr. Sandborn, who also reported the results earlier this year in Europe.

[email protected]

On Twitter@pwendl

WASHINGTON – One of the many comorbidities of cirrhosis is hepatic encephalopathy and its development is insidious. Often the patient is unaware and symptoms may not be so obvious to the physician that testing seems imperative, according to Dr. Jasmohan Bajaj of Virginia Commonwealth University in Richmond and McGuire VAMC.

He and his coworkers have developed an easy-to-use smartphone screening tool that tests the patient’s cognitive speed and flexibility, which physicians can administer themselves without having to refer the patient to psychiatric services. Currently, the need for a referral often means that these end-stage liver patients are not screened or treated for hepatic encephalopathy until their cognitive symptoms are overt.

Dr. Bajaj has received support or consulting fees from, or has been on advisory committees for, Merz, Otsuka, Salix, and Grifols.

[email protected]

WASHINGTON – One of the many comorbidities of cirrhosis is hepatic encephalopathy and its development is insidious. Often the patient is unaware and symptoms may not be so obvious to the physician that testing seems imperative, according to Dr. Jasmohan Bajaj of Virginia Commonwealth University in Richmond and McGuire VAMC.

He and his coworkers have developed an easy-to-use smartphone screening tool that tests the patient’s cognitive speed and flexibility, which physicians can administer themselves without having to refer the patient to psychiatric services. Currently, the need for a referral often means that these end-stage liver patients are not screened or treated for hepatic encephalopathy until their cognitive symptoms are overt.

Dr. Bajaj has received support or consulting fees from, or has been on advisory committees for, Merz, Otsuka, Salix, and Grifols.

[email protected]

WASHINGTON – One of the many comorbidities of cirrhosis is hepatic encephalopathy and its development is insidious. Often the patient is unaware and symptoms may not be so obvious to the physician that testing seems imperative, according to Dr. Jasmohan Bajaj of Virginia Commonwealth University in Richmond and McGuire VAMC.

He and his coworkers have developed an easy-to-use smartphone screening tool that tests the patient’s cognitive speed and flexibility, which physicians can administer themselves without having to refer the patient to psychiatric services. Currently, the need for a referral often means that these end-stage liver patients are not screened or treated for hepatic encephalopathy until their cognitive symptoms are overt.

Dr. Bajaj has received support or consulting fees from, or has been on advisory committees for, Merz, Otsuka, Salix, and Grifols.

[email protected]

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 (NCGS) 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 NCGS, GLUTOXenrolled 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 (IBS), 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 GFD 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, Italy, 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 IBS, 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 IBS, 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 NCGS.

Session co-moderatorDr. 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.

The study was funded by Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico. Dr. Elli reported consulting fees from and serving on an advisory committee or review panel for the Dr. Schär Institute.

[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 (NCGS) 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 NCGS, GLUTOXenrolled 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 (IBS), 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 GFD 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, Italy, 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 IBS, 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 IBS, 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 NCGS.

Session co-moderatorDr. 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.

The study was funded by Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico. Dr. Elli reported consulting fees from and serving on an advisory committee or review panel for the Dr. Schär Institute.

[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 (NCGS) 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 NCGS, GLUTOXenrolled 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 (IBS), 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 GFD 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, Italy, 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 IBS, 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 IBS, 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 NCGS.

Session co-moderatorDr. 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.

The study was funded by Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico. Dr. Elli reported consulting fees from and serving on an advisory committee or review panel for the Dr. Schär Institute.

[email protected]

On Twitter @pwendl

WASHINGTON – Your patient has cirrhosis, platelets 60,000 mm³, an INR of 2.0, serum creatinine of 1.2 mg/dL, and requires an endoscopic retrograde cholangiopancreatography with sphincterotomy.

What do you do next?

Management of a patient such as this is challenging, but not just because of the long-perceived risk for bleeding, Dr. Patrick S. Kamath of the Mayo Clinic in Rochester, Minn., said during a clinical symposium at the annual Digestive Disease Week.

Several other factors must be considered, including the clotting risk in patients with liver disease and the fact that procedure-related bleeding risk cannot be adequately determined preprocedure. Transfusions also carry their own dangers in this patient population and should be approached with caution, he said.

To hear more from this world-renowned liver expert, check out our interview as we sat down with Dr. Kamath at this year’s DDW.

Dr. Kamath reported no relevant financial conflicts.

[email protected]

On Twitter @pwendl

WASHINGTON – Your patient has cirrhosis, platelets 60,000 mm³, an INR of 2.0, serum creatinine of 1.2 mg/dL, and requires an endoscopic retrograde cholangiopancreatography with sphincterotomy.

What do you do next?

Management of a patient such as this is challenging, but not just because of the long-perceived risk for bleeding, Dr. Patrick S. Kamath of the Mayo Clinic in Rochester, Minn., said during a clinical symposium at the annual Digestive Disease Week.

Several other factors must be considered, including the clotting risk in patients with liver disease and the fact that procedure-related bleeding risk cannot be adequately determined preprocedure. Transfusions also carry their own dangers in this patient population and should be approached with caution, he said.

To hear more from this world-renowned liver expert, check out our interview as we sat down with Dr. Kamath at this year’s DDW.

Dr. Kamath reported no relevant financial conflicts.

[email protected]

On Twitter @pwendl

WASHINGTON – Your patient has cirrhosis, platelets 60,000 mm³, an INR of 2.0, serum creatinine of 1.2 mg/dL, and requires an endoscopic retrograde cholangiopancreatography with sphincterotomy.

What do you do next?

Management of a patient such as this is challenging, but not just because of the long-perceived risk for bleeding, Dr. Patrick S. Kamath of the Mayo Clinic in Rochester, Minn., said during a clinical symposium at the annual Digestive Disease Week.

Several other factors must be considered, including the clotting risk in patients with liver disease and the fact that procedure-related bleeding risk cannot be adequately determined preprocedure. Transfusions also carry their own dangers in this patient population and should be approached with caution, he said.

To hear more from this world-renowned liver expert, check out our interview as we sat down with Dr. Kamath at this year’s DDW.

Dr. Kamath reported no relevant financial conflicts.

[email protected]

On Twitter @pwendl

The human papillomavirus vaccine may afford protection to some women with prior HPV exposure, based on the results of a post-hoc analysis of the HPV Vaccine Trial in Costa Rica.

At the 4-year follow-up visit, multi-site efficacy against HPV16/18 DNA at the cervical, anal, or oral region was, as expected, the strongest at 84% among HPV-naive women who received the vaccine, but significant multi-site efficacy of 58% also was seen among women with evidence of HPV exposure prior to vaccination. Vaccine efficacy was nonsignificant at 25% in women with active cervical infection at vaccination, indicating that the vaccine is not therapeutic, study author Daniel C. Beachler, Ph.D., reported at the annual meeting of the American Association for Cancer Research.

© 2015 AACR/Todd Buchanan

The findings support current U.S. guidelines from the Centers for Disease Control and Prevention recommending routine vaccination for those aged 11-12 years, and vaccination through age 26 for those not previously vaccinated. HPV vaccination is known to be highly effective at cervical, anal, and oral regions in HPV-naive individuals and to have reduced impact in women aged 18-25.

What’s unknown is the combined multi-site vaccine efficacy on an individual basis, and whether HPV vaccine protects noninfected sites against HPV infection, Dr. Beachler, a postdoctoral fellow in the Infections and Immunoepidemiology Branch of the National Cancer Institute, said.

The phase III, National Cancer Institute HPV Vaccine Trial in Costa Rica enrolled 7,466 women, aged 18-25 years, over 6 months and randomly assigned them to one of three doses of the HPV16/18 vaccine (Cervarix) or to a hepatitis A vaccine (Havrix). Cervical samples were collected at every annual visit. Oral and anal samples were collected at only the 4-year follow-up visit. A total of 4,186 women contributed samples for all three sites and were included in the analysis.

Samples were tested for alpha mucosal HPV DNA types utilizing the SPF10 PCR-DEIA-LiPA25 system, version 1. An HPV event was defined as a woman with prevalent HPV16/18 DNA at the cervical, anal, or oral regions.

HPV naive was defined as HPV 16/18 seronegative and cervical HPV 16/18 DNA negative, prior infection was defined as HPV 16/18 antibody positive and cervical HPV 16/18 DNA negative, and active infection was defined as cervical HPV16/18 DNA positive.

Among all 4,186 women, multi-site vaccine efficacy at the 4-year visit was 65%, Dr. Beachler said.

HPV vaccinated women had fewer concordant infections, with vaccine efficacy reaching 91% for protection of at least two or three sites.

Indeed, only 7% of HPV 16/18-infected women in the vaccine arm had that same HPV type at two or more anatomic sites, compared with 30% of HPV 16/18-infected women in the control arm (P value < .01), again “giving support that the vaccine may provide some protection against uninfected sites in previously exposed women,” Dr. Beachler said.

He pointed out that the one-time sampling of oral and anal HPV and misclassification in assays could have affected the results. If complete information were available, vaccine efficacy would likely have been closer to 100% in the HPV-naive subgroup, he said.

Follow-up is continuing in the trial to determine the duration of protection, but there is still strong evidence of protection at 9 years, suggesting a booster dose is not necessary, Dr. Beachler said.

Further research of HPV infection outside the cervix, however, is very much needed.

“We know that only a certain percentage, 60%-70% of people who are infected, actually develop a serological response. We don’t even really know if an oral HPV infection or an anal HPV infection produces a serological response. We really need to understand HPV outside the cervix,” he said.

The National Cancer Institute funded the study. GlaxoSmithKline provided vaccines and support for regulatory aspects of the trial. Dr. Beachler declared no financial disclosures.

[email protected]

On Twitter @pwendl

The human papillomavirus vaccine may afford protection to some women with prior HPV exposure, based on the results of a post-hoc analysis of the HPV Vaccine Trial in Costa Rica.

At the 4-year follow-up visit, multi-site efficacy against HPV16/18 DNA at the cervical, anal, or oral region was, as expected, the strongest at 84% among HPV-naive women who received the vaccine, but significant multi-site efficacy of 58% also was seen among women with evidence of HPV exposure prior to vaccination. Vaccine efficacy was nonsignificant at 25% in women with active cervical infection at vaccination, indicating that the vaccine is not therapeutic, study author Daniel C. Beachler, Ph.D., reported at the annual meeting of the American Association for Cancer Research.

© 2015 AACR/Todd Buchanan

The findings support current U.S. guidelines from the Centers for Disease Control and Prevention recommending routine vaccination for those aged 11-12 years, and vaccination through age 26 for those not previously vaccinated. HPV vaccination is known to be highly effective at cervical, anal, and oral regions in HPV-naive individuals and to have reduced impact in women aged 18-25.

What’s unknown is the combined multi-site vaccine efficacy on an individual basis, and whether HPV vaccine protects noninfected sites against HPV infection, Dr. Beachler, a postdoctoral fellow in the Infections and Immunoepidemiology Branch of the National Cancer Institute, said.

The phase III, National Cancer Institute HPV Vaccine Trial in Costa Rica enrolled 7,466 women, aged 18-25 years, over 6 months and randomly assigned them to one of three doses of the HPV16/18 vaccine (Cervarix) or to a hepatitis A vaccine (Havrix). Cervical samples were collected at every annual visit. Oral and anal samples were collected at only the 4-year follow-up visit. A total of 4,186 women contributed samples for all three sites and were included in the analysis.

Samples were tested for alpha mucosal HPV DNA types utilizing the SPF10 PCR-DEIA-LiPA25 system, version 1. An HPV event was defined as a woman with prevalent HPV16/18 DNA at the cervical, anal, or oral regions.

HPV naive was defined as HPV 16/18 seronegative and cervical HPV 16/18 DNA negative, prior infection was defined as HPV 16/18 antibody positive and cervical HPV 16/18 DNA negative, and active infection was defined as cervical HPV16/18 DNA positive.

Among all 4,186 women, multi-site vaccine efficacy at the 4-year visit was 65%, Dr. Beachler said.

HPV vaccinated women had fewer concordant infections, with vaccine efficacy reaching 91% for protection of at least two or three sites.

Indeed, only 7% of HPV 16/18-infected women in the vaccine arm had that same HPV type at two or more anatomic sites, compared with 30% of HPV 16/18-infected women in the control arm (P value < .01), again “giving support that the vaccine may provide some protection against uninfected sites in previously exposed women,” Dr. Beachler said.

He pointed out that the one-time sampling of oral and anal HPV and misclassification in assays could have affected the results. If complete information were available, vaccine efficacy would likely have been closer to 100% in the HPV-naive subgroup, he said.

Follow-up is continuing in the trial to determine the duration of protection, but there is still strong evidence of protection at 9 years, suggesting a booster dose is not necessary, Dr. Beachler said.

Further research of HPV infection outside the cervix, however, is very much needed.

“We know that only a certain percentage, 60%-70% of people who are infected, actually develop a serological response. We don’t even really know if an oral HPV infection or an anal HPV infection produces a serological response. We really need to understand HPV outside the cervix,” he said.

The National Cancer Institute funded the study. GlaxoSmithKline provided vaccines and support for regulatory aspects of the trial. Dr. Beachler declared no financial disclosures.

[email protected]

On Twitter @pwendl

The human papillomavirus vaccine may afford protection to some women with prior HPV exposure, based on the results of a post-hoc analysis of the HPV Vaccine Trial in Costa Rica.

At the 4-year follow-up visit, multi-site efficacy against HPV16/18 DNA at the cervical, anal, or oral region was, as expected, the strongest at 84% among HPV-naive women who received the vaccine, but significant multi-site efficacy of 58% also was seen among women with evidence of HPV exposure prior to vaccination. Vaccine efficacy was nonsignificant at 25% in women with active cervical infection at vaccination, indicating that the vaccine is not therapeutic, study author Daniel C. Beachler, Ph.D., reported at the annual meeting of the American Association for Cancer Research.

© 2015 AACR/Todd Buchanan

The findings support current U.S. guidelines from the Centers for Disease Control and Prevention recommending routine vaccination for those aged 11-12 years, and vaccination through age 26 for those not previously vaccinated. HPV vaccination is known to be highly effective at cervical, anal, and oral regions in HPV-naive individuals and to have reduced impact in women aged 18-25.

What’s unknown is the combined multi-site vaccine efficacy on an individual basis, and whether HPV vaccine protects noninfected sites against HPV infection, Dr. Beachler, a postdoctoral fellow in the Infections and Immunoepidemiology Branch of the National Cancer Institute, said.

The phase III, National Cancer Institute HPV Vaccine Trial in Costa Rica enrolled 7,466 women, aged 18-25 years, over 6 months and randomly assigned them to one of three doses of the HPV16/18 vaccine (Cervarix) or to a hepatitis A vaccine (Havrix). Cervical samples were collected at every annual visit. Oral and anal samples were collected at only the 4-year follow-up visit. A total of 4,186 women contributed samples for all three sites and were included in the analysis.

Samples were tested for alpha mucosal HPV DNA types utilizing the SPF10 PCR-DEIA-LiPA25 system, version 1. An HPV event was defined as a woman with prevalent HPV16/18 DNA at the cervical, anal, or oral regions.

HPV naive was defined as HPV 16/18 seronegative and cervical HPV 16/18 DNA negative, prior infection was defined as HPV 16/18 antibody positive and cervical HPV 16/18 DNA negative, and active infection was defined as cervical HPV16/18 DNA positive.

Among all 4,186 women, multi-site vaccine efficacy at the 4-year visit was 65%, Dr. Beachler said.

HPV vaccinated women had fewer concordant infections, with vaccine efficacy reaching 91% for protection of at least two or three sites.

Indeed, only 7% of HPV 16/18-infected women in the vaccine arm had that same HPV type at two or more anatomic sites, compared with 30% of HPV 16/18-infected women in the control arm (P value < .01), again “giving support that the vaccine may provide some protection against uninfected sites in previously exposed women,” Dr. Beachler said.

He pointed out that the one-time sampling of oral and anal HPV and misclassification in assays could have affected the results. If complete information were available, vaccine efficacy would likely have been closer to 100% in the HPV-naive subgroup, he said.

Follow-up is continuing in the trial to determine the duration of protection, but there is still strong evidence of protection at 9 years, suggesting a booster dose is not necessary, Dr. Beachler said.

Further research of HPV infection outside the cervix, however, is very much needed.

“We know that only a certain percentage, 60%-70% of people who are infected, actually develop a serological response. We don’t even really know if an oral HPV infection or an anal HPV infection produces a serological response. We really need to understand HPV outside the cervix,” he said.

The National Cancer Institute funded the study. GlaxoSmithKline provided vaccines and support for regulatory aspects of the trial. Dr. Beachler declared no financial disclosures.

[email protected]

On Twitter @pwendl

CHICAGO – Rehabilitation time is directly associated with a reduced rate of contracture and a better range of motion, irrespective of the extent of burn injury, results from the prospective ACT study showed.

The Acuity, Contractures, Time (ACT) study examined outcomes and rehabilitation time in patients with burns involving 10% or less of their total body surface area (n = 177) and in those with burns involving more than 10% of total body surface area (n = 130). Joint range of motion was recorded based on cutaneous functional units at the time of discharge for all 307 patients enrolled from September 2010 through December 2013 at five verified burn centers across the United States. Most patients were men (71%).

Patrice Wendling/Frontline Medical News

Overall, 79% of the patients had burn scar contracture. Based on range of motion for 8,068 joints analyzed, 66% had burn scar contracture.

For patients with burns affecting 10% or less of their bodies, only rehabilitation time per cutaneous functional unit significantly differed between those with and without burn scar contracture (4.6 minutes vs. 2.4 minutes; P<i/>= .002). The same was true for patients with burns affecting more than 10% of their bodies (3.3 minutes vs. 1.4 minutes; P<i/> < .0001).

“One of the impetuses to do this study in this manner was the realization of what most therapists say all the time: They don’t have enough time to treat their patients in the hospital,” Reg Richard, P.T., said at the annual meeting of the American Burn Association.

During a discussion of the study at the meeting, Mr. Richard said he hoped the results would be used to improve rehabilitation services for burn patients and called on the ABA to lead the charge.

ABA President David Ahrenholz of Regions Hospital Burn Center, St. Paul, Minn., said in an interview that coverage of rehabilitation services varies from insurer to insurer, and physicians can’t point to an absolute number to say this is the minimum number of rehabilitation days needed to obtain a good outcome in a specific patient.

“This is the first pass of an unbelievably large data set,” Dr. Ahrenholz said “I think it will be transformative ... to help the insurers to understand that it isn’t just a number of sessions, but that we’re looking for an outcome and that the therapy should continue until we get the desired outcome.”

In the ACT study, a univariate analysis found patients with no contracture were significantly more likely than those with contracture to have shorter hospital stays (12 days vs. 14 days; P value = .02), burns with a lower percentage of body surface area involvement (5% vs. nearly 10%; P<i/> < .0001), fewer skin grafts (2.3% vs. 4%; P<i/> = .001), more rehabilitation time per total body surface area involvement (6.1 minutes vs. 4.5 minutes; P<i/> = .003 ), and more rehabilitation time per cutaneous functional unit (4.4 minutes vs. 2 minutes; P<i/> < .0001), Mr. Richard from the U.S. Army Institute of Surgical Research, JBSA Fort Sam Houston, Texas, reported.

In multivariate regression analysis, rehabilitation time per cutaneous functional unit was the only significant predictor of preventing burn scar contracture and lost range of motion for patients with small burns (Odds ratio, 1.07; 95% confidence interval, 1.02-1.12) and for those with larger burns (OR, 1.36; 95% CI, 1.18-1.74).

Further analyses are warranted, as the results were based on the variables used and present analysis methods, he said.

[email protected]

On Twitter @pwendl

CHICAGO – Rehabilitation time is directly associated with a reduced rate of contracture and a better range of motion, irrespective of the extent of burn injury, results from the prospective ACT study showed.

The Acuity, Contractures, Time (ACT) study examined outcomes and rehabilitation time in patients with burns involving 10% or less of their total body surface area (n = 177) and in those with burns involving more than 10% of total body surface area (n = 130). Joint range of motion was recorded based on cutaneous functional units at the time of discharge for all 307 patients enrolled from September 2010 through December 2013 at five verified burn centers across the United States. Most patients were men (71%).

Patrice Wendling/Frontline Medical News

Overall, 79% of the patients had burn scar contracture. Based on range of motion for 8,068 joints analyzed, 66% had burn scar contracture.

For patients with burns affecting 10% or less of their bodies, only rehabilitation time per cutaneous functional unit significantly differed between those with and without burn scar contracture (4.6 minutes vs. 2.4 minutes; P<i/>= .002). The same was true for patients with burns affecting more than 10% of their bodies (3.3 minutes vs. 1.4 minutes; P<i/> < .0001).

“One of the impetuses to do this study in this manner was the realization of what most therapists say all the time: They don’t have enough time to treat their patients in the hospital,” Reg Richard, P.T., said at the annual meeting of the American Burn Association.

During a discussion of the study at the meeting, Mr. Richard said he hoped the results would be used to improve rehabilitation services for burn patients and called on the ABA to lead the charge.

ABA President David Ahrenholz of Regions Hospital Burn Center, St. Paul, Minn., said in an interview that coverage of rehabilitation services varies from insurer to insurer, and physicians can’t point to an absolute number to say this is the minimum number of rehabilitation days needed to obtain a good outcome in a specific patient.

“This is the first pass of an unbelievably large data set,” Dr. Ahrenholz said “I think it will be transformative ... to help the insurers to understand that it isn’t just a number of sessions, but that we’re looking for an outcome and that the therapy should continue until we get the desired outcome.”

In the ACT study, a univariate analysis found patients with no contracture were significantly more likely than those with contracture to have shorter hospital stays (12 days vs. 14 days; P value = .02), burns with a lower percentage of body surface area involvement (5% vs. nearly 10%; P<i/> < .0001), fewer skin grafts (2.3% vs. 4%; P<i/> = .001), more rehabilitation time per total body surface area involvement (6.1 minutes vs. 4.5 minutes; P<i/> = .003 ), and more rehabilitation time per cutaneous functional unit (4.4 minutes vs. 2 minutes; P<i/> < .0001), Mr. Richard from the U.S. Army Institute of Surgical Research, JBSA Fort Sam Houston, Texas, reported.

In multivariate regression analysis, rehabilitation time per cutaneous functional unit was the only significant predictor of preventing burn scar contracture and lost range of motion for patients with small burns (Odds ratio, 1.07; 95% confidence interval, 1.02-1.12) and for those with larger burns (OR, 1.36; 95% CI, 1.18-1.74).

Further analyses are warranted, as the results were based on the variables used and present analysis methods, he said.

[email protected]

On Twitter @pwendl

CHICAGO – Rehabilitation time is directly associated with a reduced rate of contracture and a better range of motion, irrespective of the extent of burn injury, results from the prospective ACT study showed.

The Acuity, Contractures, Time (ACT) study examined outcomes and rehabilitation time in patients with burns involving 10% or less of their total body surface area (n = 177) and in those with burns involving more than 10% of total body surface area (n = 130). Joint range of motion was recorded based on cutaneous functional units at the time of discharge for all 307 patients enrolled from September 2010 through December 2013 at five verified burn centers across the United States. Most patients were men (71%).

Patrice Wendling/Frontline Medical News

Overall, 79% of the patients had burn scar contracture. Based on range of motion for 8,068 joints analyzed, 66% had burn scar contracture.

For patients with burns affecting 10% or less of their bodies, only rehabilitation time per cutaneous functional unit significantly differed between those with and without burn scar contracture (4.6 minutes vs. 2.4 minutes; P<i/>= .002). The same was true for patients with burns affecting more than 10% of their bodies (3.3 minutes vs. 1.4 minutes; P<i/> < .0001).

“One of the impetuses to do this study in this manner was the realization of what most therapists say all the time: They don’t have enough time to treat their patients in the hospital,” Reg Richard, P.T., said at the annual meeting of the American Burn Association.

During a discussion of the study at the meeting, Mr. Richard said he hoped the results would be used to improve rehabilitation services for burn patients and called on the ABA to lead the charge.

ABA President David Ahrenholz of Regions Hospital Burn Center, St. Paul, Minn., said in an interview that coverage of rehabilitation services varies from insurer to insurer, and physicians can’t point to an absolute number to say this is the minimum number of rehabilitation days needed to obtain a good outcome in a specific patient.

“This is the first pass of an unbelievably large data set,” Dr. Ahrenholz said “I think it will be transformative ... to help the insurers to understand that it isn’t just a number of sessions, but that we’re looking for an outcome and that the therapy should continue until we get the desired outcome.”

In the ACT study, a univariate analysis found patients with no contracture were significantly more likely than those with contracture to have shorter hospital stays (12 days vs. 14 days; P value = .02), burns with a lower percentage of body surface area involvement (5% vs. nearly 10%; P<i/> < .0001), fewer skin grafts (2.3% vs. 4%; P<i/> = .001), more rehabilitation time per total body surface area involvement (6.1 minutes vs. 4.5 minutes; P<i/> = .003 ), and more rehabilitation time per cutaneous functional unit (4.4 minutes vs. 2 minutes; P<i/> < .0001), Mr. Richard from the U.S. Army Institute of Surgical Research, JBSA Fort Sam Houston, Texas, reported.

In multivariate regression analysis, rehabilitation time per cutaneous functional unit was the only significant predictor of preventing burn scar contracture and lost range of motion for patients with small burns (Odds ratio, 1.07; 95% confidence interval, 1.02-1.12) and for those with larger burns (OR, 1.36; 95% CI, 1.18-1.74).

Further analyses are warranted, as the results were based on the variables used and present analysis methods, he said.

[email protected]

On Twitter @pwendl

Weight loss is a strong predictor of death in rheumatoid arthritis, with the greatest risk of death in low body mass index patients who were previously obese.

“Our study is the first to demonstrate a strong and independent association between recent weight loss, as opposed to BMI per se, and risk of subsequent death in patients with RA. These observations represent an important step in explaining the ‘obesity paradox’ observed in this disease,” Dr. Joshua F. Baker and his colleagues wrote in a study published online May 4 in Arthritis & Rheumatology (doi:10.1002/art.39136).

Although obesity is associated with a higher incidence of a number of diseases, including cardiovascular disease, diabetes, and certain cancers, several epidemiologic studies in the elderly and chronic disease states have reported that overweight patients may have lower mortality than normal-weight patients.

More recent evidence, however, suggests that weight loss due to the development of chronic illness is a significant confounder and may explain the seemingly protective effect of obesity on mortality. Studies that fail to consider weight loss that occurs in chronic illnesses such as RA are likely to underestimate causal associations between greater weight and death, noted Dr. Baker, a rheumatologist at the University of Pennsylvania, Philadelphia, and the Philadelphia VA Medical Center.

To unravel the “obesity paradox” in RA, the investigators examined multiple BMI measures over time and date of death for 1,674 patients with rheumatologist-diagnosed RA in the Veterans Affairs Rheumatoid Arthritis registry. The annualized rate of change in BMI was determined from the slope of BMI over time over all available visits in the preceding 13 months. Cox multivariable proportional hazard models assessed associations between BMI measures and mortality.

At enrollment, the average duration of RA was 7.4 years, average C-reactive protein was 0.8 mg/dL, average BMI was 28.5 kg/m², and maximum BMI was 33.3 kg/m^². The cohort’s average age was 63.5 years and 91% were male.

Among the 1,674 patients, there were 312 deaths in 9,183 person-years of follow-up. The median follow-up was 5.5 years, and the median interval between visits was 105 days.

A modest decline in BMI of ≥1 kg/m^² over the preceding observation period was associated with an increased risk of death before and after adjustment for multiple potential confounders, including demographics, comorbidities, BMI, smoking, and RA therapies (hazard ratio, 1.99; P < .001), Dr. Baker reported.

This remained significant in a subsample of observation periods after further adjustment for C-reactive protein and physical function (HR, 1.81; P < .001).

The analysis revealed a dose-dependent increase in the risk of death based on the annualized rate of decrease in BMI, he noted.

A loss of less than 2 kg/m^² of BMI per year did not have an increased risk of death in the subsequent observation period after multivariable adjustment (HR, 1.12; P = .4). In contrast, a loss of 2-3 kg/m^² of BMI per year increased the risk of death by about 1.5 times (HR, 1.65; P = .02) and a loss of more than 3 kg/m^² per year was associated with the greatest risk of death (HR, 2.49; P < .001).

“This observation supports the common dogma that more rapid weight loss is a poor prognostic sign, while slower changes should be less alarming,” the authors wrote.

In multivariable models, maximum BMI was not associated with risk of death (HR, 1.00; P = .80).

In models including both current and maximum BMI, however, a lower current BMI and greater maximum BMI category were each independently associated with a greater risk of death, Dr. Baker and his associates reported.

Among patients with a similar maximum BMI, a low current BMI of less than 20 kg/m^² is associated with a greater risk of death (HR, 3.82; P < .001). Similarly, among patients with a similar current BMI, those with an obese maximum BMI over 30 kg/m^² were at an increased risk of death (HR, 2.22; P = .001).

This suggests that a patient with a low BMI at a given visit and a history of BMI in the obese range is at a dramatically increased risk of death, compared with a normal-weight patient with a consistently normal weight (HR, 8.52; P < .001), the authors reported.

Overall, the observations do not support a biologically protective role of obesity in RA and support close monitoring of patients with RA who demonstrate unintentional weight loss, they concluded.

“The next steps in this area are to understand more specifically how body composition may change over time in the disease and how this may tie in with the observations here with weight loss and the obesity paradox,” Dr. Baker said in an interview. “In general, I think it is important to understand how weight and body composition changes themselves impact long-term outcomes such as comorbid disease, fractures, cardiovascular disease, and death.”

The VARA registry is supported by the Nebraska Arthritis Outcomes Research Center at the University of Nebraska Medical Center and by the Veterans Affairs Health Services Research and Development Program of the Veterans Health Administration. The investigators were supported by awards from the VA, a Rheumatology Research Foundation Investigator Award, and the National Institute of Arthritis and Musculoskeletal and Skin Disorders.

[email protected]

On Twitter @pwendl

Weight loss is a strong predictor of death in rheumatoid arthritis, with the greatest risk of death in low body mass index patients who were previously obese.

“Our study is the first to demonstrate a strong and independent association between recent weight loss, as opposed to BMI per se, and risk of subsequent death in patients with RA. These observations represent an important step in explaining the ‘obesity paradox’ observed in this disease,” Dr. Joshua F. Baker and his colleagues wrote in a study published online May 4 in Arthritis & Rheumatology (doi:10.1002/art.39136).

Although obesity is associated with a higher incidence of a number of diseases, including cardiovascular disease, diabetes, and certain cancers, several epidemiologic studies in the elderly and chronic disease states have reported that overweight patients may have lower mortality than normal-weight patients.

More recent evidence, however, suggests that weight loss due to the development of chronic illness is a significant confounder and may explain the seemingly protective effect of obesity on mortality. Studies that fail to consider weight loss that occurs in chronic illnesses such as RA are likely to underestimate causal associations between greater weight and death, noted Dr. Baker, a rheumatologist at the University of Pennsylvania, Philadelphia, and the Philadelphia VA Medical Center.

To unravel the “obesity paradox” in RA, the investigators examined multiple BMI measures over time and date of death for 1,674 patients with rheumatologist-diagnosed RA in the Veterans Affairs Rheumatoid Arthritis registry. The annualized rate of change in BMI was determined from the slope of BMI over time over all available visits in the preceding 13 months. Cox multivariable proportional hazard models assessed associations between BMI measures and mortality.

At enrollment, the average duration of RA was 7.4 years, average C-reactive protein was 0.8 mg/dL, average BMI was 28.5 kg/m², and maximum BMI was 33.3 kg/m^². The cohort’s average age was 63.5 years and 91% were male.

Among the 1,674 patients, there were 312 deaths in 9,183 person-years of follow-up. The median follow-up was 5.5 years, and the median interval between visits was 105 days.

A modest decline in BMI of ≥1 kg/m^² over the preceding observation period was associated with an increased risk of death before and after adjustment for multiple potential confounders, including demographics, comorbidities, BMI, smoking, and RA therapies (hazard ratio, 1.99; P < .001), Dr. Baker reported.

This remained significant in a subsample of observation periods after further adjustment for C-reactive protein and physical function (HR, 1.81; P < .001).

The analysis revealed a dose-dependent increase in the risk of death based on the annualized rate of decrease in BMI, he noted.

A loss of less than 2 kg/m^² of BMI per year did not have an increased risk of death in the subsequent observation period after multivariable adjustment (HR, 1.12; P = .4). In contrast, a loss of 2-3 kg/m^² of BMI per year increased the risk of death by about 1.5 times (HR, 1.65; P = .02) and a loss of more than 3 kg/m^² per year was associated with the greatest risk of death (HR, 2.49; P < .001).

“This observation supports the common dogma that more rapid weight loss is a poor prognostic sign, while slower changes should be less alarming,” the authors wrote.

In multivariable models, maximum BMI was not associated with risk of death (HR, 1.00; P = .80).

In models including both current and maximum BMI, however, a lower current BMI and greater maximum BMI category were each independently associated with a greater risk of death, Dr. Baker and his associates reported.

Among patients with a similar maximum BMI, a low current BMI of less than 20 kg/m^² is associated with a greater risk of death (HR, 3.82; P < .001). Similarly, among patients with a similar current BMI, those with an obese maximum BMI over 30 kg/m^² were at an increased risk of death (HR, 2.22; P = .001).

This suggests that a patient with a low BMI at a given visit and a history of BMI in the obese range is at a dramatically increased risk of death, compared with a normal-weight patient with a consistently normal weight (HR, 8.52; P < .001), the authors reported.

Overall, the observations do not support a biologically protective role of obesity in RA and support close monitoring of patients with RA who demonstrate unintentional weight loss, they concluded.

“The next steps in this area are to understand more specifically how body composition may change over time in the disease and how this may tie in with the observations here with weight loss and the obesity paradox,” Dr. Baker said in an interview. “In general, I think it is important to understand how weight and body composition changes themselves impact long-term outcomes such as comorbid disease, fractures, cardiovascular disease, and death.”

The VARA registry is supported by the Nebraska Arthritis Outcomes Research Center at the University of Nebraska Medical Center and by the Veterans Affairs Health Services Research and Development Program of the Veterans Health Administration. The investigators were supported by awards from the VA, a Rheumatology Research Foundation Investigator Award, and the National Institute of Arthritis and Musculoskeletal and Skin Disorders.

[email protected]

On Twitter @pwendl

Weight loss is a strong predictor of death in rheumatoid arthritis, with the greatest risk of death in low body mass index patients who were previously obese.

“Our study is the first to demonstrate a strong and independent association between recent weight loss, as opposed to BMI per se, and risk of subsequent death in patients with RA. These observations represent an important step in explaining the ‘obesity paradox’ observed in this disease,” Dr. Joshua F. Baker and his colleagues wrote in a study published online May 4 in Arthritis & Rheumatology (doi:10.1002/art.39136).

Although obesity is associated with a higher incidence of a number of diseases, including cardiovascular disease, diabetes, and certain cancers, several epidemiologic studies in the elderly and chronic disease states have reported that overweight patients may have lower mortality than normal-weight patients.

More recent evidence, however, suggests that weight loss due to the development of chronic illness is a significant confounder and may explain the seemingly protective effect of obesity on mortality. Studies that fail to consider weight loss that occurs in chronic illnesses such as RA are likely to underestimate causal associations between greater weight and death, noted Dr. Baker, a rheumatologist at the University of Pennsylvania, Philadelphia, and the Philadelphia VA Medical Center.

To unravel the “obesity paradox” in RA, the investigators examined multiple BMI measures over time and date of death for 1,674 patients with rheumatologist-diagnosed RA in the Veterans Affairs Rheumatoid Arthritis registry. The annualized rate of change in BMI was determined from the slope of BMI over time over all available visits in the preceding 13 months. Cox multivariable proportional hazard models assessed associations between BMI measures and mortality.

At enrollment, the average duration of RA was 7.4 years, average C-reactive protein was 0.8 mg/dL, average BMI was 28.5 kg/m², and maximum BMI was 33.3 kg/m^². The cohort’s average age was 63.5 years and 91% were male.

Among the 1,674 patients, there were 312 deaths in 9,183 person-years of follow-up. The median follow-up was 5.5 years, and the median interval between visits was 105 days.

A modest decline in BMI of ≥1 kg/m^² over the preceding observation period was associated with an increased risk of death before and after adjustment for multiple potential confounders, including demographics, comorbidities, BMI, smoking, and RA therapies (hazard ratio, 1.99; P < .001), Dr. Baker reported.

This remained significant in a subsample of observation periods after further adjustment for C-reactive protein and physical function (HR, 1.81; P < .001).

The analysis revealed a dose-dependent increase in the risk of death based on the annualized rate of decrease in BMI, he noted.

A loss of less than 2 kg/m^² of BMI per year did not have an increased risk of death in the subsequent observation period after multivariable adjustment (HR, 1.12; P = .4). In contrast, a loss of 2-3 kg/m^² of BMI per year increased the risk of death by about 1.5 times (HR, 1.65; P = .02) and a loss of more than 3 kg/m^² per year was associated with the greatest risk of death (HR, 2.49; P < .001).

“This observation supports the common dogma that more rapid weight loss is a poor prognostic sign, while slower changes should be less alarming,” the authors wrote.

In multivariable models, maximum BMI was not associated with risk of death (HR, 1.00; P = .80).

In models including both current and maximum BMI, however, a lower current BMI and greater maximum BMI category were each independently associated with a greater risk of death, Dr. Baker and his associates reported.

Among patients with a similar maximum BMI, a low current BMI of less than 20 kg/m^² is associated with a greater risk of death (HR, 3.82; P < .001). Similarly, among patients with a similar current BMI, those with an obese maximum BMI over 30 kg/m^² were at an increased risk of death (HR, 2.22; P = .001).

This suggests that a patient with a low BMI at a given visit and a history of BMI in the obese range is at a dramatically increased risk of death, compared with a normal-weight patient with a consistently normal weight (HR, 8.52; P < .001), the authors reported.

Overall, the observations do not support a biologically protective role of obesity in RA and support close monitoring of patients with RA who demonstrate unintentional weight loss, they concluded.

“The next steps in this area are to understand more specifically how body composition may change over time in the disease and how this may tie in with the observations here with weight loss and the obesity paradox,” Dr. Baker said in an interview. “In general, I think it is important to understand how weight and body composition changes themselves impact long-term outcomes such as comorbid disease, fractures, cardiovascular disease, and death.”

The VARA registry is supported by the Nebraska Arthritis Outcomes Research Center at the University of Nebraska Medical Center and by the Veterans Affairs Health Services Research and Development Program of the Veterans Health Administration. The investigators were supported by awards from the VA, a Rheumatology Research Foundation Investigator Award, and the National Institute of Arthritis and Musculoskeletal and Skin Disorders.

[email protected]

On Twitter @pwendl

The first-in-class immunotherapy IMCgp100 was active in late-stage melanoma, particularly ocular melanoma, in an ongoing, phase I/IIa trial.

Four of 14 patients treated with a weekly regimen in the phase IIa portion of the trial had a partial or complete response by RECIST 1.1, including two partial responses persisting more than 18 months.

© 2015 AACR/Todd Buchanan

Responses were observed across a variety of anatomical sites including liver and lung, and in patients refractory to ipilimumab (Yervoy) and pembrolizumab (Keytruda), “suggesting efficacy beyond the use of emerging and licensed treatments for melanoma,” principal investigator Dr. Mark Middleton said at the annual meeting of the American Association for Cancer Research.

The two shorter-lived responses – a partial response for 5.9 months and a complete response for 4.7 months – were in patients with ocular melanoma. One had been treated with surgery only, but the other had significant prior therapy and progressed through surgery, chemotherapy, radiation, and ipilimumab, he said. A third uveal melanoma patient left the trial after receiving what was later determined to be a nontolerated dose.

Progression-free survival in the two ocular melanoma responders was 9 months and 12 months, which bears up very well, compared with chemotherapy and data reported last year with MEK inhibition (JAMA 2014;311:2397-2405), said Dr. Middleton of the University of Oxford, England.

Invited discussant Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, commented that the responses were impressive.

“Anyone who’s treated ocular melanoma knows that if there’s a bad disease out there, this is one,” Dr. Ribas said. “It’s the subtype of melanoma that would not respond to any of the other immunotherapies and now we’re seeing responses here.”

The study enrolled patients with stage IV or unresectable stage III melanoma who were HLA-A2 (human leukocyte antigen-A2) positive and had no standard therapeutic options or had an appropriate window between alternative therapeutic options.

Patients had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, three-fourths had M1c disease, and 16 had prior exposure to immunotherapy.

The phase I portion of the trial was designed to determine the maximum tolerated dose (MTD) of IMCgp100, with results reported at last year’s AACR.

IMCgp100 was dosed using a weekly regimen or a high-intensity regimen consisting of four consecutive daily doses in 3-week cycles. The maximum tolerated dose (MTD) for weekly administration was 600 nanograms/kilogram, which was converted to a flat dose of 50 mcg. Dose escalation of the high-intensity regimen is ongoing.

IMCgp100 contains an enhanced T-cell receptor and an anti-CD3 antibody fragment and is designed to redirect T cells to kill gp100-positive melanoma cells.

There is no clear correlation as yet between gp100 expression as measured by immunohistochemistry in the tumors because one patient who measured negative has a response at one of the lower dose levels, Dr. Middleton said.

“This isn’t a CLIA [Clinical Laboratory Improvement Amendments]-validated test, so the value of this, in particular, when taking relatively small samples is uncertain, and our working hypothesis has to be that gp100 expression is required in order to see an effective therapeutic response, albeit the ability to measure it remains uncertain,” he said.

Four dose-limiting toxicities, predominantly grade 3 or 4 hypotension, have been reported and emerged first at the 405 mg/kg dose. Most events resolved within 1-3 days.

One grade 4 hypotension was associated with associated acute respiratory distress syndrome and severe dyspnea in a patient on the MTD and resolved after intensive supportive care. With additional experience managing the potential for hypotension, however, there has been no significant hypotension at the MTD in the expansion phase, Dr. Middleton observed.

A phase 1b/II trial is being planned to evaluate IMCgp100 in combination with the anti–programmed death ligand-1 antibody MEDI4736 and/or the anti-CTLA-4 antibody tremelimumab in metastatic melanoma, according to a recent joint statement from Immunocore, developer of IMCgp100, and MedImmune.

[email protected]

On Twitter @pwendl

The first-in-class immunotherapy IMCgp100 was active in late-stage melanoma, particularly ocular melanoma, in an ongoing, phase I/IIa trial.

Four of 14 patients treated with a weekly regimen in the phase IIa portion of the trial had a partial or complete response by RECIST 1.1, including two partial responses persisting more than 18 months.

© 2015 AACR/Todd Buchanan

Responses were observed across a variety of anatomical sites including liver and lung, and in patients refractory to ipilimumab (Yervoy) and pembrolizumab (Keytruda), “suggesting efficacy beyond the use of emerging and licensed treatments for melanoma,” principal investigator Dr. Mark Middleton said at the annual meeting of the American Association for Cancer Research.

The two shorter-lived responses – a partial response for 5.9 months and a complete response for 4.7 months – were in patients with ocular melanoma. One had been treated with surgery only, but the other had significant prior therapy and progressed through surgery, chemotherapy, radiation, and ipilimumab, he said. A third uveal melanoma patient left the trial after receiving what was later determined to be a nontolerated dose.

Progression-free survival in the two ocular melanoma responders was 9 months and 12 months, which bears up very well, compared with chemotherapy and data reported last year with MEK inhibition (JAMA 2014;311:2397-2405), said Dr. Middleton of the University of Oxford, England.

Invited discussant Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, commented that the responses were impressive.

“Anyone who’s treated ocular melanoma knows that if there’s a bad disease out there, this is one,” Dr. Ribas said. “It’s the subtype of melanoma that would not respond to any of the other immunotherapies and now we’re seeing responses here.”

The study enrolled patients with stage IV or unresectable stage III melanoma who were HLA-A2 (human leukocyte antigen-A2) positive and had no standard therapeutic options or had an appropriate window between alternative therapeutic options.

Patients had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, three-fourths had M1c disease, and 16 had prior exposure to immunotherapy.

The phase I portion of the trial was designed to determine the maximum tolerated dose (MTD) of IMCgp100, with results reported at last year’s AACR.

IMCgp100 was dosed using a weekly regimen or a high-intensity regimen consisting of four consecutive daily doses in 3-week cycles. The maximum tolerated dose (MTD) for weekly administration was 600 nanograms/kilogram, which was converted to a flat dose of 50 mcg. Dose escalation of the high-intensity regimen is ongoing.

IMCgp100 contains an enhanced T-cell receptor and an anti-CD3 antibody fragment and is designed to redirect T cells to kill gp100-positive melanoma cells.

There is no clear correlation as yet between gp100 expression as measured by immunohistochemistry in the tumors because one patient who measured negative has a response at one of the lower dose levels, Dr. Middleton said.

“This isn’t a CLIA [Clinical Laboratory Improvement Amendments]-validated test, so the value of this, in particular, when taking relatively small samples is uncertain, and our working hypothesis has to be that gp100 expression is required in order to see an effective therapeutic response, albeit the ability to measure it remains uncertain,” he said.

Four dose-limiting toxicities, predominantly grade 3 or 4 hypotension, have been reported and emerged first at the 405 mg/kg dose. Most events resolved within 1-3 days.

One grade 4 hypotension was associated with associated acute respiratory distress syndrome and severe dyspnea in a patient on the MTD and resolved after intensive supportive care. With additional experience managing the potential for hypotension, however, there has been no significant hypotension at the MTD in the expansion phase, Dr. Middleton observed.

A phase 1b/II trial is being planned to evaluate IMCgp100 in combination with the anti–programmed death ligand-1 antibody MEDI4736 and/or the anti-CTLA-4 antibody tremelimumab in metastatic melanoma, according to a recent joint statement from Immunocore, developer of IMCgp100, and MedImmune.

[email protected]

On Twitter @pwendl

The first-in-class immunotherapy IMCgp100 was active in late-stage melanoma, particularly ocular melanoma, in an ongoing, phase I/IIa trial.

Four of 14 patients treated with a weekly regimen in the phase IIa portion of the trial had a partial or complete response by RECIST 1.1, including two partial responses persisting more than 18 months.

© 2015 AACR/Todd Buchanan

Responses were observed across a variety of anatomical sites including liver and lung, and in patients refractory to ipilimumab (Yervoy) and pembrolizumab (Keytruda), “suggesting efficacy beyond the use of emerging and licensed treatments for melanoma,” principal investigator Dr. Mark Middleton said at the annual meeting of the American Association for Cancer Research.

The two shorter-lived responses – a partial response for 5.9 months and a complete response for 4.7 months – were in patients with ocular melanoma. One had been treated with surgery only, but the other had significant prior therapy and progressed through surgery, chemotherapy, radiation, and ipilimumab, he said. A third uveal melanoma patient left the trial after receiving what was later determined to be a nontolerated dose.

Progression-free survival in the two ocular melanoma responders was 9 months and 12 months, which bears up very well, compared with chemotherapy and data reported last year with MEK inhibition (JAMA 2014;311:2397-2405), said Dr. Middleton of the University of Oxford, England.

Invited discussant Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, commented that the responses were impressive.

“Anyone who’s treated ocular melanoma knows that if there’s a bad disease out there, this is one,” Dr. Ribas said. “It’s the subtype of melanoma that would not respond to any of the other immunotherapies and now we’re seeing responses here.”

The study enrolled patients with stage IV or unresectable stage III melanoma who were HLA-A2 (human leukocyte antigen-A2) positive and had no standard therapeutic options or had an appropriate window between alternative therapeutic options.

Patients had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, three-fourths had M1c disease, and 16 had prior exposure to immunotherapy.

The phase I portion of the trial was designed to determine the maximum tolerated dose (MTD) of IMCgp100, with results reported at last year’s AACR.

IMCgp100 was dosed using a weekly regimen or a high-intensity regimen consisting of four consecutive daily doses in 3-week cycles. The maximum tolerated dose (MTD) for weekly administration was 600 nanograms/kilogram, which was converted to a flat dose of 50 mcg. Dose escalation of the high-intensity regimen is ongoing.

IMCgp100 contains an enhanced T-cell receptor and an anti-CD3 antibody fragment and is designed to redirect T cells to kill gp100-positive melanoma cells.

There is no clear correlation as yet between gp100 expression as measured by immunohistochemistry in the tumors because one patient who measured negative has a response at one of the lower dose levels, Dr. Middleton said.

“This isn’t a CLIA [Clinical Laboratory Improvement Amendments]-validated test, so the value of this, in particular, when taking relatively small samples is uncertain, and our working hypothesis has to be that gp100 expression is required in order to see an effective therapeutic response, albeit the ability to measure it remains uncertain,” he said.

Four dose-limiting toxicities, predominantly grade 3 or 4 hypotension, have been reported and emerged first at the 405 mg/kg dose. Most events resolved within 1-3 days.

One grade 4 hypotension was associated with associated acute respiratory distress syndrome and severe dyspnea in a patient on the MTD and resolved after intensive supportive care. With additional experience managing the potential for hypotension, however, there has been no significant hypotension at the MTD in the expansion phase, Dr. Middleton observed.

A phase 1b/II trial is being planned to evaluate IMCgp100 in combination with the anti–programmed death ligand-1 antibody MEDI4736 and/or the anti-CTLA-4 antibody tremelimumab in metastatic melanoma, according to a recent joint statement from Immunocore, developer of IMCgp100, and MedImmune.

[email protected]

On Twitter @pwendl