Ankylosing spondylitis

A biosimilar agent to Remicade, the brand-name and reference form of infliximab, stayed on track to become the second biosimilar drug to enter the U.S. market when the Arthritis Advisory Committee of the Food and Drug Administration voted overwhelmingly in favor of licensure of the biosimilar at a meeting on Feb. 9.

The vote was 21 in favor and 3 against, with no abstentions.

Because of the way the FDA staff worded the question that the Advisory Committee voted on, the panel not only was in favor of approving biosimilar licensure but also recommended that license for six of the seven diverse indications that Remicade currently has: treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, adult and pediatric Crohn’s disease, and adult ulcerative colitis. The panel did not vote on licensing the biosimilar for treatment of pediatric ulcerative colitis because that specific indication for Remicade remains on patent for a few more years.

The broad range of indications for which the Committee recommended approval was notable because the formulation of biosimilar infliximab under review, manufactured by Celltrion and known in the United States as CT-P13, had been clinically studied only in patients with rheumatoid arthritis or ankylosing spondylitis. The other four recommended indications represented extrapolations, based on the totality of biosimilar evidence presented at the meeting by both Celltrion staffers and consultants as well as analyses presented by FDA staff members.

The overall thrust of the extrapolation issue was that if biosimilarity to Remicade was proven by a range of preclinical and clinical testing, and if safety and efficacy similar to Remicade was shown in trials that enrolled only patients with rheumatoid arthritis or ankylosing spondylitis, then the safety and efficacy previously proven for Remicade for the other indications could be reasonably extrapolated to apply to CT-P13 also, even though CT-P13 was never tested on patients with those conditions. This turned out to often be the key issue that panel members grappled with as they decided whether to vote in favor of the question the FDA asked them to address.

“Many of us are uncomfortable with this new pathway” of extrapolation, said panel member Dr. Beth L. Jonas, a rheumatologist at the University of North Carolina at Chapel Hill.

“I feel we’re taking a risk” with the extrapolations, said Dr. Mary E. Maloney, professor of medicine and chief of dermatology at the University of Massachusetts in Worcester. “We have a responsibility to take a risk to provide biosimilars to patients and to reduce their cost” for needed treatments, she said during the Committee’s discussion of their votes.

“Biosimilar is a new concept, but it’s the future of how we will look at drugs,” explained panel member Dr. Wilma Bergfeld, professor of dermatology at the Cleveland Clinic.

CT-P13 is currently marketed in many other countries worldwide under the brand names Remsima or Inflectra.

The FDA’s staff was clearly behind this application. After summarizing the agency’s internal analysis of the data submitted by Celltrion, Dr. Nikolay Nikolov, clinical team leader for the FDA’s Division of Pulmonary, Allergy and Rheumatology Products, concluded that “the totality of evidence provided by the applicant supports a conclusion that CT-P13 is biosimilar to U.S.-licensed Remicade,” and that “scientific justification for extrapolating the clinical data supports a finding of biosimilarity for all indications for which U.S.-licensed Remicade is licensed.” The FDA’s position makes it seem very likely that the agency will accept the Advisory Committee’s vote and grant CT-P13 license for U.S. marketing in the near future.

CT-P13 also received support during the public comment period of the Committee’s deliberations. At that time, Dr. Gideon P. Smith, a dermatologist at Massachusetts General Hospital in Boston spoke on behalf of the American Academy of Dermatology Association. “Biologics are some of the most important recent developments in treating plaque psoriasis, but cost is an important issue. We hope that biosimilars will decrease the cost of this treatment,” Dr. Smith said. “Infliximab is a complex molecule with a complex production process. We are concerned about the safety and efficacy of treatment. The AADA supports approval based on reducing cost and improving patient access. However, we strongly recommend caution through long-term postmarketing surveillance and using registry data to identify issues of immunogenicity, efficacy, and safety that were not seen in the clinical trials.”

The drug also received support from Dr. Angus B. Worthing, who represented the American College of Rheumatology. “Biosimilars may be the only tool to keep prices of biologics within reason,” said Dr. Worthing, a rheumatologist in Washington. But he also stressed that “extrapolation should be done with caution and not routinely granted.”

CT-P13 has the potential to make a fairly widely used biologic significantly more affordable. In countries where it has come onto the market, it’s been priced at roughly 30% below the prevailing cost of Remicade prior to this competition.

“Infliximab is an extremely important tool in our armamentarium for treatment of both ulcerative colitis and Crohn’s disease,” commented Dr. Stephen B. Hanauer, professor of gastroenterology and hepatology at Northwestern University in Chicago. “Biologic therapies account for an increasing proportion of health care costs for chronic diseases such as inflammatory bowel disease and reducing these costs will be important as increasing numbers of patients are benefiting from long-term biologic therapies. Having reviewed the extensive preclinical and clinical data with CT-P13, I am comfortable with potential substitution or switching as long as physicians are aware of the change and can track any potential reactions to the administered product,” he said in an interview.

“Infliximab is currently used by U.S. rheumatologists to treat certain patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. It is not the most-widely used tumor necrosis factor inhibitor, which is adalimumab, but it is often used. After FDA approval, biosimilar infliximab is anticipated to be priced lower than Remicade and that would likely increase use of infliximab for rheumatologic conditions,” said Dr. Jonathan Kay, a rheumatologist and professor of medicine at the University of Massachusetts in Worcester. “The clinical experience with CT-P13 in trials and in routine use in other countries show no significant loss of efficacy or any other major problem when changing patients from Remicade to CT-P13. All the data suggest that CT-P13 is highly similar to the reference product. It’s almost akin to comparing one lot of Remicade to another lot of Remicade. I personally would not have a problem initiating a patient on CT-P13 if infliximab was the appropriate drug to use,” Dr. Kay said in an interview.

Dr. Hanauer has been a consultant to Celltrion. Dr. Kay has been a consultant to several drug companies.

[email protected]

On Twitter @mitchelzoler

A biosimilar agent to Remicade, the brand-name and reference form of infliximab, stayed on track to become the second biosimilar drug to enter the U.S. market when the Arthritis Advisory Committee of the Food and Drug Administration voted overwhelmingly in favor of licensure of the biosimilar at a meeting on Feb. 9.

The vote was 21 in favor and 3 against, with no abstentions.

Because of the way the FDA staff worded the question that the Advisory Committee voted on, the panel not only was in favor of approving biosimilar licensure but also recommended that license for six of the seven diverse indications that Remicade currently has: treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, adult and pediatric Crohn’s disease, and adult ulcerative colitis. The panel did not vote on licensing the biosimilar for treatment of pediatric ulcerative colitis because that specific indication for Remicade remains on patent for a few more years.

The broad range of indications for which the Committee recommended approval was notable because the formulation of biosimilar infliximab under review, manufactured by Celltrion and known in the United States as CT-P13, had been clinically studied only in patients with rheumatoid arthritis or ankylosing spondylitis. The other four recommended indications represented extrapolations, based on the totality of biosimilar evidence presented at the meeting by both Celltrion staffers and consultants as well as analyses presented by FDA staff members.

The overall thrust of the extrapolation issue was that if biosimilarity to Remicade was proven by a range of preclinical and clinical testing, and if safety and efficacy similar to Remicade was shown in trials that enrolled only patients with rheumatoid arthritis or ankylosing spondylitis, then the safety and efficacy previously proven for Remicade for the other indications could be reasonably extrapolated to apply to CT-P13 also, even though CT-P13 was never tested on patients with those conditions. This turned out to often be the key issue that panel members grappled with as they decided whether to vote in favor of the question the FDA asked them to address.

“Many of us are uncomfortable with this new pathway” of extrapolation, said panel member Dr. Beth L. Jonas, a rheumatologist at the University of North Carolina at Chapel Hill.

“I feel we’re taking a risk” with the extrapolations, said Dr. Mary E. Maloney, professor of medicine and chief of dermatology at the University of Massachusetts in Worcester. “We have a responsibility to take a risk to provide biosimilars to patients and to reduce their cost” for needed treatments, she said during the Committee’s discussion of their votes.

“Biosimilar is a new concept, but it’s the future of how we will look at drugs,” explained panel member Dr. Wilma Bergfeld, professor of dermatology at the Cleveland Clinic.

CT-P13 is currently marketed in many other countries worldwide under the brand names Remsima or Inflectra.

The FDA’s staff was clearly behind this application. After summarizing the agency’s internal analysis of the data submitted by Celltrion, Dr. Nikolay Nikolov, clinical team leader for the FDA’s Division of Pulmonary, Allergy and Rheumatology Products, concluded that “the totality of evidence provided by the applicant supports a conclusion that CT-P13 is biosimilar to U.S.-licensed Remicade,” and that “scientific justification for extrapolating the clinical data supports a finding of biosimilarity for all indications for which U.S.-licensed Remicade is licensed.” The FDA’s position makes it seem very likely that the agency will accept the Advisory Committee’s vote and grant CT-P13 license for U.S. marketing in the near future.

CT-P13 also received support during the public comment period of the Committee’s deliberations. At that time, Dr. Gideon P. Smith, a dermatologist at Massachusetts General Hospital in Boston spoke on behalf of the American Academy of Dermatology Association. “Biologics are some of the most important recent developments in treating plaque psoriasis, but cost is an important issue. We hope that biosimilars will decrease the cost of this treatment,” Dr. Smith said. “Infliximab is a complex molecule with a complex production process. We are concerned about the safety and efficacy of treatment. The AADA supports approval based on reducing cost and improving patient access. However, we strongly recommend caution through long-term postmarketing surveillance and using registry data to identify issues of immunogenicity, efficacy, and safety that were not seen in the clinical trials.”

The drug also received support from Dr. Angus B. Worthing, who represented the American College of Rheumatology. “Biosimilars may be the only tool to keep prices of biologics within reason,” said Dr. Worthing, a rheumatologist in Washington. But he also stressed that “extrapolation should be done with caution and not routinely granted.”

CT-P13 has the potential to make a fairly widely used biologic significantly more affordable. In countries where it has come onto the market, it’s been priced at roughly 30% below the prevailing cost of Remicade prior to this competition.

“Infliximab is an extremely important tool in our armamentarium for treatment of both ulcerative colitis and Crohn’s disease,” commented Dr. Stephen B. Hanauer, professor of gastroenterology and hepatology at Northwestern University in Chicago. “Biologic therapies account for an increasing proportion of health care costs for chronic diseases such as inflammatory bowel disease and reducing these costs will be important as increasing numbers of patients are benefiting from long-term biologic therapies. Having reviewed the extensive preclinical and clinical data with CT-P13, I am comfortable with potential substitution or switching as long as physicians are aware of the change and can track any potential reactions to the administered product,” he said in an interview.

“Infliximab is currently used by U.S. rheumatologists to treat certain patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. It is not the most-widely used tumor necrosis factor inhibitor, which is adalimumab, but it is often used. After FDA approval, biosimilar infliximab is anticipated to be priced lower than Remicade and that would likely increase use of infliximab for rheumatologic conditions,” said Dr. Jonathan Kay, a rheumatologist and professor of medicine at the University of Massachusetts in Worcester. “The clinical experience with CT-P13 in trials and in routine use in other countries show no significant loss of efficacy or any other major problem when changing patients from Remicade to CT-P13. All the data suggest that CT-P13 is highly similar to the reference product. It’s almost akin to comparing one lot of Remicade to another lot of Remicade. I personally would not have a problem initiating a patient on CT-P13 if infliximab was the appropriate drug to use,” Dr. Kay said in an interview.

Dr. Hanauer has been a consultant to Celltrion. Dr. Kay has been a consultant to several drug companies.

[email protected]

On Twitter @mitchelzoler

A biosimilar agent to Remicade, the brand-name and reference form of infliximab, stayed on track to become the second biosimilar drug to enter the U.S. market when the Arthritis Advisory Committee of the Food and Drug Administration voted overwhelmingly in favor of licensure of the biosimilar at a meeting on Feb. 9.

The vote was 21 in favor and 3 against, with no abstentions.

Because of the way the FDA staff worded the question that the Advisory Committee voted on, the panel not only was in favor of approving biosimilar licensure but also recommended that license for six of the seven diverse indications that Remicade currently has: treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, adult and pediatric Crohn’s disease, and adult ulcerative colitis. The panel did not vote on licensing the biosimilar for treatment of pediatric ulcerative colitis because that specific indication for Remicade remains on patent for a few more years.

The broad range of indications for which the Committee recommended approval was notable because the formulation of biosimilar infliximab under review, manufactured by Celltrion and known in the United States as CT-P13, had been clinically studied only in patients with rheumatoid arthritis or ankylosing spondylitis. The other four recommended indications represented extrapolations, based on the totality of biosimilar evidence presented at the meeting by both Celltrion staffers and consultants as well as analyses presented by FDA staff members.

The overall thrust of the extrapolation issue was that if biosimilarity to Remicade was proven by a range of preclinical and clinical testing, and if safety and efficacy similar to Remicade was shown in trials that enrolled only patients with rheumatoid arthritis or ankylosing spondylitis, then the safety and efficacy previously proven for Remicade for the other indications could be reasonably extrapolated to apply to CT-P13 also, even though CT-P13 was never tested on patients with those conditions. This turned out to often be the key issue that panel members grappled with as they decided whether to vote in favor of the question the FDA asked them to address.

“Many of us are uncomfortable with this new pathway” of extrapolation, said panel member Dr. Beth L. Jonas, a rheumatologist at the University of North Carolina at Chapel Hill.

“I feel we’re taking a risk” with the extrapolations, said Dr. Mary E. Maloney, professor of medicine and chief of dermatology at the University of Massachusetts in Worcester. “We have a responsibility to take a risk to provide biosimilars to patients and to reduce their cost” for needed treatments, she said during the Committee’s discussion of their votes.

“Biosimilar is a new concept, but it’s the future of how we will look at drugs,” explained panel member Dr. Wilma Bergfeld, professor of dermatology at the Cleveland Clinic.

CT-P13 is currently marketed in many other countries worldwide under the brand names Remsima or Inflectra.

The FDA’s staff was clearly behind this application. After summarizing the agency’s internal analysis of the data submitted by Celltrion, Dr. Nikolay Nikolov, clinical team leader for the FDA’s Division of Pulmonary, Allergy and Rheumatology Products, concluded that “the totality of evidence provided by the applicant supports a conclusion that CT-P13 is biosimilar to U.S.-licensed Remicade,” and that “scientific justification for extrapolating the clinical data supports a finding of biosimilarity for all indications for which U.S.-licensed Remicade is licensed.” The FDA’s position makes it seem very likely that the agency will accept the Advisory Committee’s vote and grant CT-P13 license for U.S. marketing in the near future.

CT-P13 also received support during the public comment period of the Committee’s deliberations. At that time, Dr. Gideon P. Smith, a dermatologist at Massachusetts General Hospital in Boston spoke on behalf of the American Academy of Dermatology Association. “Biologics are some of the most important recent developments in treating plaque psoriasis, but cost is an important issue. We hope that biosimilars will decrease the cost of this treatment,” Dr. Smith said. “Infliximab is a complex molecule with a complex production process. We are concerned about the safety and efficacy of treatment. The AADA supports approval based on reducing cost and improving patient access. However, we strongly recommend caution through long-term postmarketing surveillance and using registry data to identify issues of immunogenicity, efficacy, and safety that were not seen in the clinical trials.”

The drug also received support from Dr. Angus B. Worthing, who represented the American College of Rheumatology. “Biosimilars may be the only tool to keep prices of biologics within reason,” said Dr. Worthing, a rheumatologist in Washington. But he also stressed that “extrapolation should be done with caution and not routinely granted.”

CT-P13 has the potential to make a fairly widely used biologic significantly more affordable. In countries where it has come onto the market, it’s been priced at roughly 30% below the prevailing cost of Remicade prior to this competition.

“Infliximab is an extremely important tool in our armamentarium for treatment of both ulcerative colitis and Crohn’s disease,” commented Dr. Stephen B. Hanauer, professor of gastroenterology and hepatology at Northwestern University in Chicago. “Biologic therapies account for an increasing proportion of health care costs for chronic diseases such as inflammatory bowel disease and reducing these costs will be important as increasing numbers of patients are benefiting from long-term biologic therapies. Having reviewed the extensive preclinical and clinical data with CT-P13, I am comfortable with potential substitution or switching as long as physicians are aware of the change and can track any potential reactions to the administered product,” he said in an interview.

“Infliximab is currently used by U.S. rheumatologists to treat certain patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. It is not the most-widely used tumor necrosis factor inhibitor, which is adalimumab, but it is often used. After FDA approval, biosimilar infliximab is anticipated to be priced lower than Remicade and that would likely increase use of infliximab for rheumatologic conditions,” said Dr. Jonathan Kay, a rheumatologist and professor of medicine at the University of Massachusetts in Worcester. “The clinical experience with CT-P13 in trials and in routine use in other countries show no significant loss of efficacy or any other major problem when changing patients from Remicade to CT-P13. All the data suggest that CT-P13 is highly similar to the reference product. It’s almost akin to comparing one lot of Remicade to another lot of Remicade. I personally would not have a problem initiating a patient on CT-P13 if infliximab was the appropriate drug to use,” Dr. Kay said in an interview.

Dr. Hanauer has been a consultant to Celltrion. Dr. Kay has been a consultant to several drug companies.

[email protected]

On Twitter @mitchelzoler

People under the age of 45 with chronic back pain for more than 3 months can be reliably identified as having axial spondyloarthritis (axSpA) if they have one or more of three SpA disease features, researchers report in Arthritis & Rheumatology.

The research team, led by rheumatologist Dr. Atul Deodhar from Oregon Health & Science University in Portland, noted that results of the German MASTER study indicated that among undiagnosed patients with chronic back pain starting before the age of 45 the presence of inflammatory back pain, human leukocyte antigen B27 (HLA-B27), and/or sacroiliitis on imaging was a reliable screening method for axSpA.

However, the authors said, there is limited information on the epidemiology of axSpA, which encompasses ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA), in the United States. Both AS and nr-axSpA typically go undiagnosed for many years, but AS is more easily identified by the presence of sacroiliitis on radiographs.

In order to determine if the German research finding applied to the U.S. population, the researchers conducted the Prevalence of Axial SpA (PROSpA) trial, involving 751 patients from 68 rheumatology centers who were either existing patients in rheumatology practices, new referrals, or were self-referred.

Participants were required to have chronic back pain for 3 or more months beginning at less than 45 years of age and have one or more of three SpA features: 1. positive HLA-B27; 2. current inflammatory back pain; and 3. MRI/x-ray evidence of sacroiliitis, and no prior SpA diagnosis.

Medical history/physical exam, pelvic x-ray, MRI of sacroiliac joints, C-reactive protein, and HLA-B27 were collected and rheumatologists were asked if a clinical diagnosis of axSpA could be made based upon results. 

Results showed that out of a total of 697 patients, 319 (46%) were given a clinical diagnosis of axSpA by the rheumatologist (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39612).

Of 744 patients, 348 (47%) fulfilled Assessment of SpondyloArthritis International Society (ASAS) criteria. Of these, 238 were classified as nr-axSpA, and 108 were classified as having AS based on fulfillment of the modified New York criteria. (Two patients had missing data.)

Additionally, 238 (32%) patients were categorized as having nr-axSpA, and 396 patients did not fulfill ASAS criteria or the modified New York criteria for AS.

The specificity and sensitivity of the ASAS criteria are reported at 84% and 83%. About 80% of the patients who received a clinical diagnosis of axSpA also fulfilled the ASAS axSpA criteria. The specificity and sensitivity of the criteria in this study were 79% (95% confidence interval, 75%-83%) and 81% (95% CI, 77%-85%), respectively.

The researchers noted that the majority of patients who received a diagnosis from a rheumatologist fulfilled the imaging arm of the ASAS criteria, whereas those who did not receive a diagnosis fulfilled the clinical arm.

“This observation highlights the need for accurate interpretation of MRI images in clinical practice given the importance of MRI imaging for evaluation of patients for axial SpA,” they wrote.

Overall, the findings emphasized the need to improve the identification and diagnosis of both AS and nr-axSpA among patients already receiving care in rheumatology practices and those newly referred to rheumatologists, the researchers said.

“These patients experience similar burden of disease and can remain undiagnosed, and therefore, untreated, for many years,” they wrote.

Indeed, the data indicated that some of the patients included in the study had symptoms for an average of 14 years, they said.

People under the age of 45 with chronic back pain for more than 3 months can be reliably identified as having axial spondyloarthritis (axSpA) if they have one or more of three SpA disease features, researchers report in Arthritis & Rheumatology.

The research team, led by rheumatologist Dr. Atul Deodhar from Oregon Health & Science University in Portland, noted that results of the German MASTER study indicated that among undiagnosed patients with chronic back pain starting before the age of 45 the presence of inflammatory back pain, human leukocyte antigen B27 (HLA-B27), and/or sacroiliitis on imaging was a reliable screening method for axSpA.

However, the authors said, there is limited information on the epidemiology of axSpA, which encompasses ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA), in the United States. Both AS and nr-axSpA typically go undiagnosed for many years, but AS is more easily identified by the presence of sacroiliitis on radiographs.

In order to determine if the German research finding applied to the U.S. population, the researchers conducted the Prevalence of Axial SpA (PROSpA) trial, involving 751 patients from 68 rheumatology centers who were either existing patients in rheumatology practices, new referrals, or were self-referred.

Participants were required to have chronic back pain for 3 or more months beginning at less than 45 years of age and have one or more of three SpA features: 1. positive HLA-B27; 2. current inflammatory back pain; and 3. MRI/x-ray evidence of sacroiliitis, and no prior SpA diagnosis.

Medical history/physical exam, pelvic x-ray, MRI of sacroiliac joints, C-reactive protein, and HLA-B27 were collected and rheumatologists were asked if a clinical diagnosis of axSpA could be made based upon results. 

Results showed that out of a total of 697 patients, 319 (46%) were given a clinical diagnosis of axSpA by the rheumatologist (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39612).

Of 744 patients, 348 (47%) fulfilled Assessment of SpondyloArthritis International Society (ASAS) criteria. Of these, 238 were classified as nr-axSpA, and 108 were classified as having AS based on fulfillment of the modified New York criteria. (Two patients had missing data.)

Additionally, 238 (32%) patients were categorized as having nr-axSpA, and 396 patients did not fulfill ASAS criteria or the modified New York criteria for AS.

The specificity and sensitivity of the ASAS criteria are reported at 84% and 83%. About 80% of the patients who received a clinical diagnosis of axSpA also fulfilled the ASAS axSpA criteria. The specificity and sensitivity of the criteria in this study were 79% (95% confidence interval, 75%-83%) and 81% (95% CI, 77%-85%), respectively.

The researchers noted that the majority of patients who received a diagnosis from a rheumatologist fulfilled the imaging arm of the ASAS criteria, whereas those who did not receive a diagnosis fulfilled the clinical arm.

“This observation highlights the need for accurate interpretation of MRI images in clinical practice given the importance of MRI imaging for evaluation of patients for axial SpA,” they wrote.

Overall, the findings emphasized the need to improve the identification and diagnosis of both AS and nr-axSpA among patients already receiving care in rheumatology practices and those newly referred to rheumatologists, the researchers said.

“These patients experience similar burden of disease and can remain undiagnosed, and therefore, untreated, for many years,” they wrote.

Indeed, the data indicated that some of the patients included in the study had symptoms for an average of 14 years, they said.

People under the age of 45 with chronic back pain for more than 3 months can be reliably identified as having axial spondyloarthritis (axSpA) if they have one or more of three SpA disease features, researchers report in Arthritis & Rheumatology.

The research team, led by rheumatologist Dr. Atul Deodhar from Oregon Health & Science University in Portland, noted that results of the German MASTER study indicated that among undiagnosed patients with chronic back pain starting before the age of 45 the presence of inflammatory back pain, human leukocyte antigen B27 (HLA-B27), and/or sacroiliitis on imaging was a reliable screening method for axSpA.

However, the authors said, there is limited information on the epidemiology of axSpA, which encompasses ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA), in the United States. Both AS and nr-axSpA typically go undiagnosed for many years, but AS is more easily identified by the presence of sacroiliitis on radiographs.

In order to determine if the German research finding applied to the U.S. population, the researchers conducted the Prevalence of Axial SpA (PROSpA) trial, involving 751 patients from 68 rheumatology centers who were either existing patients in rheumatology practices, new referrals, or were self-referred.

Participants were required to have chronic back pain for 3 or more months beginning at less than 45 years of age and have one or more of three SpA features: 1. positive HLA-B27; 2. current inflammatory back pain; and 3. MRI/x-ray evidence of sacroiliitis, and no prior SpA diagnosis.

Medical history/physical exam, pelvic x-ray, MRI of sacroiliac joints, C-reactive protein, and HLA-B27 were collected and rheumatologists were asked if a clinical diagnosis of axSpA could be made based upon results. 

Results showed that out of a total of 697 patients, 319 (46%) were given a clinical diagnosis of axSpA by the rheumatologist (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39612).

Of 744 patients, 348 (47%) fulfilled Assessment of SpondyloArthritis International Society (ASAS) criteria. Of these, 238 were classified as nr-axSpA, and 108 were classified as having AS based on fulfillment of the modified New York criteria. (Two patients had missing data.)

Additionally, 238 (32%) patients were categorized as having nr-axSpA, and 396 patients did not fulfill ASAS criteria or the modified New York criteria for AS.

The specificity and sensitivity of the ASAS criteria are reported at 84% and 83%. About 80% of the patients who received a clinical diagnosis of axSpA also fulfilled the ASAS axSpA criteria. The specificity and sensitivity of the criteria in this study were 79% (95% confidence interval, 75%-83%) and 81% (95% CI, 77%-85%), respectively.

The researchers noted that the majority of patients who received a diagnosis from a rheumatologist fulfilled the imaging arm of the ASAS criteria, whereas those who did not receive a diagnosis fulfilled the clinical arm.

“This observation highlights the need for accurate interpretation of MRI images in clinical practice given the importance of MRI imaging for evaluation of patients for axial SpA,” they wrote.

Overall, the findings emphasized the need to improve the identification and diagnosis of both AS and nr-axSpA among patients already receiving care in rheumatology practices and those newly referred to rheumatologists, the researchers said.

“These patients experience similar burden of disease and can remain undiagnosed, and therefore, untreated, for many years,” they wrote.

Indeed, the data indicated that some of the patients included in the study had symptoms for an average of 14 years, they said.

Current recommendations for identifying sacroiliitis on MRI to classify patients with nonradiographic axial spondyloarthritis should still depend on the presence of subchondral bone marrow edema, but additional evidence of structural lesions can be taken into account to define the presence of inflammatory lesions, according to a consensus review by experts from the Assessment in SpondyloArthritis International Society MRI working group.

The additional information provided by structural lesions, such as erosions, detected via MRI of the sacroiliac (SI) joint or spine is not necessary for the definition, but “may enhance confidence in the classification of axial SpA [spondyloarthritis],” said the panel of 16 rheumatologists, 4 radiologists, and 1 research fellow, who presented their summary and draft proposal at the January 2014 annual assembly of the Assessment in SpondyloArthritis International Society (ASAS), where members unanimously approved it (Ann Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208642).

© parisvas/Thinkstockphotos.com

The group’s goal was to examine whether new data published on axial SpA in the 5 years following the 2009 publication of the ASAS recommendations were “sufficient to merit a change in the MRI definition of a positive MRI and clarify any misunderstanding of the existing definition.”

Overall, the working group determined that the addition of “structural damage changes of the SI joints and the addition of features on MRI of the spine for classification purposes is not yet clear and this continues to be an important research agenda.”

Adding any single lesion or combination of lesions to the current classification criteria for nonradiographic axial spondyloarthritis (nr-axSpA) did not increase the sensitivity of the MRI definition without losing specificity in one cohort, whereas there was an unclear benefit to adding SI erosion to the definition in another cohort. The evaluation of these lesions on MRI depended on the use of T1 weighting and fat-suppression techniques, as well as the contextual interpretation of MRI, which currently add too much complexity to the definition of a positive SI joint MRI to be useful in achieving a “consensus for definitions for each MRI structural damage lesion and the setting of thresholds for any defined lesion or combination of lesions,” the working group wrote.

The panelists found that there was no consistent beneficial effect of adding features of SpA on spine MRI to the definition. Spine MRI added incremental sensitivity in other analyses, but also increased false-positive SpA diagnoses.

In a commentary reviewing the controversy and evidence for classifying diseases within the spectrum of axial SpA, Dr. Atul Deodhar of Oregon Health and Science University, Portland, and his colleagues noted that “there is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.” They said the need for formal distinction between nr-axSpA and ankylosing spondylitis may require some exceptions, such as when it is necessary “to specify an approved indication for TNFi [tumor necrosis factor inhibitor] therapy, when off-label use of biologics must be avoided ... and to clarify the presence of structural changes that are required for patients to receive coverage from their insurance carrier to use a TNFi” (Ann. Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208852).

The working panel and commentary authors declared having no competing interests.

[email protected]

Current recommendations for identifying sacroiliitis on MRI to classify patients with nonradiographic axial spondyloarthritis should still depend on the presence of subchondral bone marrow edema, but additional evidence of structural lesions can be taken into account to define the presence of inflammatory lesions, according to a consensus review by experts from the Assessment in SpondyloArthritis International Society MRI working group.

The additional information provided by structural lesions, such as erosions, detected via MRI of the sacroiliac (SI) joint or spine is not necessary for the definition, but “may enhance confidence in the classification of axial SpA [spondyloarthritis],” said the panel of 16 rheumatologists, 4 radiologists, and 1 research fellow, who presented their summary and draft proposal at the January 2014 annual assembly of the Assessment in SpondyloArthritis International Society (ASAS), where members unanimously approved it (Ann Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208642).

© parisvas/Thinkstockphotos.com

The group’s goal was to examine whether new data published on axial SpA in the 5 years following the 2009 publication of the ASAS recommendations were “sufficient to merit a change in the MRI definition of a positive MRI and clarify any misunderstanding of the existing definition.”

Overall, the working group determined that the addition of “structural damage changes of the SI joints and the addition of features on MRI of the spine for classification purposes is not yet clear and this continues to be an important research agenda.”

Adding any single lesion or combination of lesions to the current classification criteria for nonradiographic axial spondyloarthritis (nr-axSpA) did not increase the sensitivity of the MRI definition without losing specificity in one cohort, whereas there was an unclear benefit to adding SI erosion to the definition in another cohort. The evaluation of these lesions on MRI depended on the use of T1 weighting and fat-suppression techniques, as well as the contextual interpretation of MRI, which currently add too much complexity to the definition of a positive SI joint MRI to be useful in achieving a “consensus for definitions for each MRI structural damage lesion and the setting of thresholds for any defined lesion or combination of lesions,” the working group wrote.

The panelists found that there was no consistent beneficial effect of adding features of SpA on spine MRI to the definition. Spine MRI added incremental sensitivity in other analyses, but also increased false-positive SpA diagnoses.

In a commentary reviewing the controversy and evidence for classifying diseases within the spectrum of axial SpA, Dr. Atul Deodhar of Oregon Health and Science University, Portland, and his colleagues noted that “there is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.” They said the need for formal distinction between nr-axSpA and ankylosing spondylitis may require some exceptions, such as when it is necessary “to specify an approved indication for TNFi [tumor necrosis factor inhibitor] therapy, when off-label use of biologics must be avoided ... and to clarify the presence of structural changes that are required for patients to receive coverage from their insurance carrier to use a TNFi” (Ann. Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208852).

The working panel and commentary authors declared having no competing interests.

[email protected]

Current recommendations for identifying sacroiliitis on MRI to classify patients with nonradiographic axial spondyloarthritis should still depend on the presence of subchondral bone marrow edema, but additional evidence of structural lesions can be taken into account to define the presence of inflammatory lesions, according to a consensus review by experts from the Assessment in SpondyloArthritis International Society MRI working group.

The additional information provided by structural lesions, such as erosions, detected via MRI of the sacroiliac (SI) joint or spine is not necessary for the definition, but “may enhance confidence in the classification of axial SpA [spondyloarthritis],” said the panel of 16 rheumatologists, 4 radiologists, and 1 research fellow, who presented their summary and draft proposal at the January 2014 annual assembly of the Assessment in SpondyloArthritis International Society (ASAS), where members unanimously approved it (Ann Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208642).

© parisvas/Thinkstockphotos.com

The group’s goal was to examine whether new data published on axial SpA in the 5 years following the 2009 publication of the ASAS recommendations were “sufficient to merit a change in the MRI definition of a positive MRI and clarify any misunderstanding of the existing definition.”

Overall, the working group determined that the addition of “structural damage changes of the SI joints and the addition of features on MRI of the spine for classification purposes is not yet clear and this continues to be an important research agenda.”

Adding any single lesion or combination of lesions to the current classification criteria for nonradiographic axial spondyloarthritis (nr-axSpA) did not increase the sensitivity of the MRI definition without losing specificity in one cohort, whereas there was an unclear benefit to adding SI erosion to the definition in another cohort. The evaluation of these lesions on MRI depended on the use of T1 weighting and fat-suppression techniques, as well as the contextual interpretation of MRI, which currently add too much complexity to the definition of a positive SI joint MRI to be useful in achieving a “consensus for definitions for each MRI structural damage lesion and the setting of thresholds for any defined lesion or combination of lesions,” the working group wrote.

The panelists found that there was no consistent beneficial effect of adding features of SpA on spine MRI to the definition. Spine MRI added incremental sensitivity in other analyses, but also increased false-positive SpA diagnoses.

In a commentary reviewing the controversy and evidence for classifying diseases within the spectrum of axial SpA, Dr. Atul Deodhar of Oregon Health and Science University, Portland, and his colleagues noted that “there is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.” They said the need for formal distinction between nr-axSpA and ankylosing spondylitis may require some exceptions, such as when it is necessary “to specify an approved indication for TNFi [tumor necrosis factor inhibitor] therapy, when off-label use of biologics must be avoided ... and to clarify the presence of structural changes that are required for patients to receive coverage from their insurance carrier to use a TNFi” (Ann. Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208852).

The working panel and commentary authors declared having no competing interests.

[email protected]

The effectiveness of immunoglobulin biologic treatments in controlling chronic and potentially debilitating autoimmune diseases such as rheumatoid arthritis and ulcerative colitis means that more physicians are faced with the question of how to handle the use of these drugs in pregnancy.

While immunoglobulin G (IgG) biologicals are large molecules, there is no doubt that they cross the placenta through specific transport systems with a long half life in infants, creating potential risks for immunocompromise in early life. At the same time, these biologicals are essential, in many cases, for controlling the pregnant woman’s disease and allowing her to carry a pregnancy successfully by avoiding disease flare.

For ob.gyns., successful management of a pregnancy in which the woman is taking an immunoglobulin biological, such as an anti–tumor necrosis factor (TNF)-alpha agent, requires an understanding of not only which drugs cross the placenta, but when they do so and at what levels.

Crossing the placenta

Along with my student Juejing Ling, I recently reviewed the question of how the use of immunoglobulin biologicals in pregnancy affects the vaccination of infants in an article published in Expert Review of Vaccines (2015 Dec 7:1-18 doi: 10.1586/14760584.2016.1115351). Our analysis relates only to biologicals with partial or full IgG structure, as they are capable of crossing the placenta.

Data are still limited about the use of immunoglobulin biologicals in pregnancy, but measurement of umbilical cord blood has shown high levels of anti-TNF IgG in newborn serum, raising concerns about how these neonates will respond to vaccinations.

Neonates rely on maternal IgG transport to prevent infection in the first few months of life and that transport process begins around 12 weeks gestation. Fetal IgG levels begin to rise at 13-18 weeks and reach 120%-130% of maternal levels when the fetus reaches full term. In contrast, fusion proteins that contain the Fc portion and Fab fragment appear to have limited ability to cross the placenta. As a result, chimeric and full human IgG antibodies such as infliximab, adalimumab, and rituximab have demonstrated high levels of placental transport, while other agents, such as etanercept, appear to cross the placenta at lower levels.

Hence, due to the ineffective clearance, certain immunoglobulin biologicals actually have a higher concentration and a longer half life in neonates than in mothers. For instance, with infliximab, studies show that levels in the umbilical cord were up to fourfold higher than maternal levels, even when the drug was discontinued at 30 weeks of pregnancy or earlier. Due to long neonatal half life, infliximab levels became undetectable in infant serum only between 2-7 months, compared with 1-2 weeks in adults. Adalimumab is similar, where concentrations of the drug in neonates can be 150% of the maternal serum level and detectable for about 3 months after birth.

Transport of anti-TNFs is also possible through breastfeeding, although studies indicate that the levels are very low.

Infection risk

Due to the immunosuppressive effect of anti-TNF immunoglobulin biologicals, newborn infection is a real concern. Review of the literature showed that severe and moderate neutropenia and skin infection were reported in four neonates born to two women with ulcerative colitis who had taken infliximab throughout pregnancy.

Some other studies have followed infants who had detectable biological levels at birth after in utero exposure. In general, there is normal development in the first year without overt infection. However, there have been case reports of infections with varicella or upper respiratory infections in infants exposed to infliximab before 30 weeks’ gestation.

There is very little data on the long-term immune system impacts for infants exposed to immunoglobulin biologicals in utero. However, these agents are generally not at detectable levels after 1 year.

Impact on vaccination

Although these IgG biologicals will clear the infants’ systems after several months of life (generally by 8 months), another concern is for how their presence in the early months impacts neonatal vaccination, specifically live attenuated vaccines such as MMR (measles, mumps and rubella), BCG for tuberculosis, oral polio, rotavirus vaccine, and the intranasal influenza vaccine.

Generally, outcomes among infants exposed to anti-TNFs have been good. For instance, reports looking at 24 children with exposure to anti-TNFs found no complications with the MMR vaccine. But a famous case report identified one infant who died at 4.5 months after receiving the BCG vaccine at 3 months. The mother, who had Crohn’s disease, had been taking infliximab 10 mg/kg every 8 weeks throughout her pregnancy.

Another study of 15 infants in the Czech Republic who were exposed to infliximab in utero and received BCG vaccination within 1 week of birth found that three of the infants developed large local skin reactions. One of the three children also developed axillary lymphadenopathy. All of the children recovered without the need for anti-tuberculosis therapy.

So what do these complications mean for vaccination strategies? Both the European Crohn’s and Colitis Organisation and the World Congress of Gastroenterology recommend that in terms of non-live vaccines, it’s safe to follow the same vaccine schedule as infants not exposed to biologicals in utero. When it comes to live attenuated vaccines such as rotavirus, oral polio, and BCG, these infants should be treated as immunocompromised and not receive these vaccines until after 6 months of age, when the biologicals should be at undetectable levels.

Future directions

Given that most infections and other adverse events happen after late exposure in pregnancy, some have recommended discontinuing anti-TNF treatment before the third trimester. In fact, this has become a common management practice. However, this should be an individualized decision made after discussion between a woman and her physician or physicians. Any benefits from early discontinuation of an immunoglobulin biological therapy should be weighed against the risk of disease flare, which also has real potential to complicate pregnancy.

The evidence presented here not only shines a light on the possible risk to infants, but also on the need for more high-quality evidence on which physicians can base decisions. Most of the available evidence is drawn from case reports and registry databases. Both of these suffer from a lack of control groups. To answer these questions definitively, we need more well-controlled studies of large populations. I strongly urge readers to follow the amazing work led by Dr. Uma Mahadevan and her colleagues at the University of California, San Francisco on biological use in pregnancy and long-term outcomes. As we wait for more evidence, we all look forward to the development of newer biologic agents that can help women control autoimmune disease without crossing the placenta.

Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having no financial disclosures related to this article. Email him at [email protected].

The effectiveness of immunoglobulin biologic treatments in controlling chronic and potentially debilitating autoimmune diseases such as rheumatoid arthritis and ulcerative colitis means that more physicians are faced with the question of how to handle the use of these drugs in pregnancy.

While immunoglobulin G (IgG) biologicals are large molecules, there is no doubt that they cross the placenta through specific transport systems with a long half life in infants, creating potential risks for immunocompromise in early life. At the same time, these biologicals are essential, in many cases, for controlling the pregnant woman’s disease and allowing her to carry a pregnancy successfully by avoiding disease flare.

For ob.gyns., successful management of a pregnancy in which the woman is taking an immunoglobulin biological, such as an anti–tumor necrosis factor (TNF)-alpha agent, requires an understanding of not only which drugs cross the placenta, but when they do so and at what levels.

Crossing the placenta

Along with my student Juejing Ling, I recently reviewed the question of how the use of immunoglobulin biologicals in pregnancy affects the vaccination of infants in an article published in Expert Review of Vaccines (2015 Dec 7:1-18 doi: 10.1586/14760584.2016.1115351). Our analysis relates only to biologicals with partial or full IgG structure, as they are capable of crossing the placenta.

Data are still limited about the use of immunoglobulin biologicals in pregnancy, but measurement of umbilical cord blood has shown high levels of anti-TNF IgG in newborn serum, raising concerns about how these neonates will respond to vaccinations.

Neonates rely on maternal IgG transport to prevent infection in the first few months of life and that transport process begins around 12 weeks gestation. Fetal IgG levels begin to rise at 13-18 weeks and reach 120%-130% of maternal levels when the fetus reaches full term. In contrast, fusion proteins that contain the Fc portion and Fab fragment appear to have limited ability to cross the placenta. As a result, chimeric and full human IgG antibodies such as infliximab, adalimumab, and rituximab have demonstrated high levels of placental transport, while other agents, such as etanercept, appear to cross the placenta at lower levels.

Hence, due to the ineffective clearance, certain immunoglobulin biologicals actually have a higher concentration and a longer half life in neonates than in mothers. For instance, with infliximab, studies show that levels in the umbilical cord were up to fourfold higher than maternal levels, even when the drug was discontinued at 30 weeks of pregnancy or earlier. Due to long neonatal half life, infliximab levels became undetectable in infant serum only between 2-7 months, compared with 1-2 weeks in adults. Adalimumab is similar, where concentrations of the drug in neonates can be 150% of the maternal serum level and detectable for about 3 months after birth.

Transport of anti-TNFs is also possible through breastfeeding, although studies indicate that the levels are very low.

Infection risk

Due to the immunosuppressive effect of anti-TNF immunoglobulin biologicals, newborn infection is a real concern. Review of the literature showed that severe and moderate neutropenia and skin infection were reported in four neonates born to two women with ulcerative colitis who had taken infliximab throughout pregnancy.

Some other studies have followed infants who had detectable biological levels at birth after in utero exposure. In general, there is normal development in the first year without overt infection. However, there have been case reports of infections with varicella or upper respiratory infections in infants exposed to infliximab before 30 weeks’ gestation.

There is very little data on the long-term immune system impacts for infants exposed to immunoglobulin biologicals in utero. However, these agents are generally not at detectable levels after 1 year.

Impact on vaccination

Although these IgG biologicals will clear the infants’ systems after several months of life (generally by 8 months), another concern is for how their presence in the early months impacts neonatal vaccination, specifically live attenuated vaccines such as MMR (measles, mumps and rubella), BCG for tuberculosis, oral polio, rotavirus vaccine, and the intranasal influenza vaccine.

Generally, outcomes among infants exposed to anti-TNFs have been good. For instance, reports looking at 24 children with exposure to anti-TNFs found no complications with the MMR vaccine. But a famous case report identified one infant who died at 4.5 months after receiving the BCG vaccine at 3 months. The mother, who had Crohn’s disease, had been taking infliximab 10 mg/kg every 8 weeks throughout her pregnancy.

Another study of 15 infants in the Czech Republic who were exposed to infliximab in utero and received BCG vaccination within 1 week of birth found that three of the infants developed large local skin reactions. One of the three children also developed axillary lymphadenopathy. All of the children recovered without the need for anti-tuberculosis therapy.

So what do these complications mean for vaccination strategies? Both the European Crohn’s and Colitis Organisation and the World Congress of Gastroenterology recommend that in terms of non-live vaccines, it’s safe to follow the same vaccine schedule as infants not exposed to biologicals in utero. When it comes to live attenuated vaccines such as rotavirus, oral polio, and BCG, these infants should be treated as immunocompromised and not receive these vaccines until after 6 months of age, when the biologicals should be at undetectable levels.

Future directions

Given that most infections and other adverse events happen after late exposure in pregnancy, some have recommended discontinuing anti-TNF treatment before the third trimester. In fact, this has become a common management practice. However, this should be an individualized decision made after discussion between a woman and her physician or physicians. Any benefits from early discontinuation of an immunoglobulin biological therapy should be weighed against the risk of disease flare, which also has real potential to complicate pregnancy.

The evidence presented here not only shines a light on the possible risk to infants, but also on the need for more high-quality evidence on which physicians can base decisions. Most of the available evidence is drawn from case reports and registry databases. Both of these suffer from a lack of control groups. To answer these questions definitively, we need more well-controlled studies of large populations. I strongly urge readers to follow the amazing work led by Dr. Uma Mahadevan and her colleagues at the University of California, San Francisco on biological use in pregnancy and long-term outcomes. As we wait for more evidence, we all look forward to the development of newer biologic agents that can help women control autoimmune disease without crossing the placenta.

Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having no financial disclosures related to this article. Email him at [email protected].

The effectiveness of immunoglobulin biologic treatments in controlling chronic and potentially debilitating autoimmune diseases such as rheumatoid arthritis and ulcerative colitis means that more physicians are faced with the question of how to handle the use of these drugs in pregnancy.

While immunoglobulin G (IgG) biologicals are large molecules, there is no doubt that they cross the placenta through specific transport systems with a long half life in infants, creating potential risks for immunocompromise in early life. At the same time, these biologicals are essential, in many cases, for controlling the pregnant woman’s disease and allowing her to carry a pregnancy successfully by avoiding disease flare.

For ob.gyns., successful management of a pregnancy in which the woman is taking an immunoglobulin biological, such as an anti–tumor necrosis factor (TNF)-alpha agent, requires an understanding of not only which drugs cross the placenta, but when they do so and at what levels.

Crossing the placenta

Along with my student Juejing Ling, I recently reviewed the question of how the use of immunoglobulin biologicals in pregnancy affects the vaccination of infants in an article published in Expert Review of Vaccines (2015 Dec 7:1-18 doi: 10.1586/14760584.2016.1115351). Our analysis relates only to biologicals with partial or full IgG structure, as they are capable of crossing the placenta.

Data are still limited about the use of immunoglobulin biologicals in pregnancy, but measurement of umbilical cord blood has shown high levels of anti-TNF IgG in newborn serum, raising concerns about how these neonates will respond to vaccinations.

Neonates rely on maternal IgG transport to prevent infection in the first few months of life and that transport process begins around 12 weeks gestation. Fetal IgG levels begin to rise at 13-18 weeks and reach 120%-130% of maternal levels when the fetus reaches full term. In contrast, fusion proteins that contain the Fc portion and Fab fragment appear to have limited ability to cross the placenta. As a result, chimeric and full human IgG antibodies such as infliximab, adalimumab, and rituximab have demonstrated high levels of placental transport, while other agents, such as etanercept, appear to cross the placenta at lower levels.

Hence, due to the ineffective clearance, certain immunoglobulin biologicals actually have a higher concentration and a longer half life in neonates than in mothers. For instance, with infliximab, studies show that levels in the umbilical cord were up to fourfold higher than maternal levels, even when the drug was discontinued at 30 weeks of pregnancy or earlier. Due to long neonatal half life, infliximab levels became undetectable in infant serum only between 2-7 months, compared with 1-2 weeks in adults. Adalimumab is similar, where concentrations of the drug in neonates can be 150% of the maternal serum level and detectable for about 3 months after birth.

Transport of anti-TNFs is also possible through breastfeeding, although studies indicate that the levels are very low.

Infection risk

Due to the immunosuppressive effect of anti-TNF immunoglobulin biologicals, newborn infection is a real concern. Review of the literature showed that severe and moderate neutropenia and skin infection were reported in four neonates born to two women with ulcerative colitis who had taken infliximab throughout pregnancy.

Some other studies have followed infants who had detectable biological levels at birth after in utero exposure. In general, there is normal development in the first year without overt infection. However, there have been case reports of infections with varicella or upper respiratory infections in infants exposed to infliximab before 30 weeks’ gestation.

There is very little data on the long-term immune system impacts for infants exposed to immunoglobulin biologicals in utero. However, these agents are generally not at detectable levels after 1 year.

Impact on vaccination

Although these IgG biologicals will clear the infants’ systems after several months of life (generally by 8 months), another concern is for how their presence in the early months impacts neonatal vaccination, specifically live attenuated vaccines such as MMR (measles, mumps and rubella), BCG for tuberculosis, oral polio, rotavirus vaccine, and the intranasal influenza vaccine.

Generally, outcomes among infants exposed to anti-TNFs have been good. For instance, reports looking at 24 children with exposure to anti-TNFs found no complications with the MMR vaccine. But a famous case report identified one infant who died at 4.5 months after receiving the BCG vaccine at 3 months. The mother, who had Crohn’s disease, had been taking infliximab 10 mg/kg every 8 weeks throughout her pregnancy.

Another study of 15 infants in the Czech Republic who were exposed to infliximab in utero and received BCG vaccination within 1 week of birth found that three of the infants developed large local skin reactions. One of the three children also developed axillary lymphadenopathy. All of the children recovered without the need for anti-tuberculosis therapy.

So what do these complications mean for vaccination strategies? Both the European Crohn’s and Colitis Organisation and the World Congress of Gastroenterology recommend that in terms of non-live vaccines, it’s safe to follow the same vaccine schedule as infants not exposed to biologicals in utero. When it comes to live attenuated vaccines such as rotavirus, oral polio, and BCG, these infants should be treated as immunocompromised and not receive these vaccines until after 6 months of age, when the biologicals should be at undetectable levels.

Future directions

Given that most infections and other adverse events happen after late exposure in pregnancy, some have recommended discontinuing anti-TNF treatment before the third trimester. In fact, this has become a common management practice. However, this should be an individualized decision made after discussion between a woman and her physician or physicians. Any benefits from early discontinuation of an immunoglobulin biological therapy should be weighed against the risk of disease flare, which also has real potential to complicate pregnancy.

The evidence presented here not only shines a light on the possible risk to infants, but also on the need for more high-quality evidence on which physicians can base decisions. Most of the available evidence is drawn from case reports and registry databases. Both of these suffer from a lack of control groups. To answer these questions definitively, we need more well-controlled studies of large populations. I strongly urge readers to follow the amazing work led by Dr. Uma Mahadevan and her colleagues at the University of California, San Francisco on biological use in pregnancy and long-term outcomes. As we wait for more evidence, we all look forward to the development of newer biologic agents that can help women control autoimmune disease without crossing the placenta.

Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having no financial disclosures related to this article. Email him at [email protected].

The Food and Drug Administration approved two new indications for the interleukin-17A inhibitor secukinumab (Cosentyx) – psoriatic arthritis in adults and ankylosing spondylitis in adults – on Jan. 15. These join the approval for moderate to severe plaque psoriasis in adults it received in January 2015, according to an announcement from the drug’s manufacturer, Novartis.

The approvals are based on the efficacy and safety outcomes from four placebo-controlled, phase III studies, which included more than 1,500 adult patients with ankylosing spondylitis (AS) or psoriatic arthritis (PsA) who were biologic treatment naive or had an inadequate response or were intolerant to anti-TNF agents.

Pivotal phase III studies in the secukinumab clinical trial program, which provided key data for the submission, were MEASURE 1 and MEASURE 2 involving 590 patients with AS, and FUTURE 1 and FUTURE 2 involving 1,003 patients with PsA. Novartis continues to investigate the fully human monoclonal antibody against IL-17A for its potential in preventing radiographic progression of spinal and joint structural damage in AS and PsA patients, respectively.

The European Medicines Agency approved secukinumab for PsA and AS in November 2015.

[email protected]

The Food and Drug Administration approved two new indications for the interleukin-17A inhibitor secukinumab (Cosentyx) – psoriatic arthritis in adults and ankylosing spondylitis in adults – on Jan. 15. These join the approval for moderate to severe plaque psoriasis in adults it received in January 2015, according to an announcement from the drug’s manufacturer, Novartis.

The approvals are based on the efficacy and safety outcomes from four placebo-controlled, phase III studies, which included more than 1,500 adult patients with ankylosing spondylitis (AS) or psoriatic arthritis (PsA) who were biologic treatment naive or had an inadequate response or were intolerant to anti-TNF agents.

Pivotal phase III studies in the secukinumab clinical trial program, which provided key data for the submission, were MEASURE 1 and MEASURE 2 involving 590 patients with AS, and FUTURE 1 and FUTURE 2 involving 1,003 patients with PsA. Novartis continues to investigate the fully human monoclonal antibody against IL-17A for its potential in preventing radiographic progression of spinal and joint structural damage in AS and PsA patients, respectively.

The European Medicines Agency approved secukinumab for PsA and AS in November 2015.

[email protected]

The Food and Drug Administration approved two new indications for the interleukin-17A inhibitor secukinumab (Cosentyx) – psoriatic arthritis in adults and ankylosing spondylitis in adults – on Jan. 15. These join the approval for moderate to severe plaque psoriasis in adults it received in January 2015, according to an announcement from the drug’s manufacturer, Novartis.

The approvals are based on the efficacy and safety outcomes from four placebo-controlled, phase III studies, which included more than 1,500 adult patients with ankylosing spondylitis (AS) or psoriatic arthritis (PsA) who were biologic treatment naive or had an inadequate response or were intolerant to anti-TNF agents.

Pivotal phase III studies in the secukinumab clinical trial program, which provided key data for the submission, were MEASURE 1 and MEASURE 2 involving 590 patients with AS, and FUTURE 1 and FUTURE 2 involving 1,003 patients with PsA. Novartis continues to investigate the fully human monoclonal antibody against IL-17A for its potential in preventing radiographic progression of spinal and joint structural damage in AS and PsA patients, respectively.

The European Medicines Agency approved secukinumab for PsA and AS in November 2015.

[email protected]

SAN FRANCISCO – Sulfasalazine prevents formation of antibodies against tumor necrosis factor inhibitors, but probably not as well as methotrexate, according to a European study of 140 axial spondyloarthritis patients.

“The effect of sulfasalazine on the development of antidrug antibodies has not been studied before. Our initial hypothesis was that methotrexate would [reduce] antibody formation” because it’s been shown to do that before, but that “sulfasalazine would not. This was a surprise to us,” said senior investigator Dr. Alejandro Balsa, chief of rheumatology at La Paz University Hospital in Madrid.

©sshepard/iStock

The findings suggest that sulfasalazine, like methotrexate, might “prevent immunogenicity and, hence ... secondary failure of” a tumor necrosis factor inhibitor (TNFi), he said at the annual meeting of the American College of Rheumatology.

Thirty-one patients (22%) were on infliximab (Remicade) and 109 (78%) were on adalimumab (Humira) in the year-long study, which was conducted in Madrid and Amsterdam.

Of the 90 patients on TNFi monotherapy, 33 (37%) developed TNFi antibodies, including 3 of 13 (23%) on infliximab monotherapy and 30 of 77 (39%) on adalimumab alone. The difference was not statistically significant.

Of the 50 patients on concomitant therapy, antibodies against anti-TNF agents occurred in 6 of 35 on sulfasalazine (17%), including three cases on infliximab and three on adalimumab. There was just one antibody case in 15 patients on methotrexate (7%); the patient was on adalimumab.

The trend toward better antibody protection with methotrexate was, again, not significant, probably because of the small numbers in the study.

Methotrexate and sulfasalazine are not routinely prescribed for axial spondyloarthritis; patients were on them in the study to help with peripheral manifestations. The drugs only prevent antibodies if started before a TNFi. “Once patients develop anti-[TNF] antibodies,” it’s too late, Dr. Balsa noted.

Despite the promising results, he said there’s not enough data at this point to recommend routine pretreatment with methotrexate or sulfasalazine to prevent TNFi antibodies.

As expected, antibodies diminished the clinical effect of a TNFi. Less than a quarter of antibody patients, versus more than a half free from antibodies, reached the investigators’ mark for low disease activity at 1 year: clinical improvement plus a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score below 4 and normal C-reactive protein (P = .03).

Also at 1 year, patients on monotherapy had an overall BASDAI improvement of about 1 point on the 10-point scale. Patients on methotrexate gained an additional point or so (P = .04), while those on sulfasalazine gained about a half point extra (P = .16).

“We only saw significant improvements in patients treated with methotrexate, probably because 100% cotreated with methotrexate had free” serum TNFi “at 1 year, as compared with only 82% cotreated with sulfasalazine,” Dr. Balsa said.

Oddly, the investigators detected free serum TNFi at 1 year in 78 (87%) monotherapy patients, which was more than in those cotreated with sulfasalazine; he didn’t address the finding.

The mean BASDAI at baseline was 6. Ankylosing spondylitis was the most common diagnosis in the study. More than half the subjects were men, the majority of patients were HLA-B27 positive, and their mean disease duration was 11 years.

Dr. Balsa’s institution receives research funding from Pfizer, UCB, and Roche, and he receives speakers fees from those companies plus AbbVie, Merck, and Bristol-Myers Squibb. Other investigators disclosed financial ties to those or other companies.

[email protected]

SAN FRANCISCO – Sulfasalazine prevents formation of antibodies against tumor necrosis factor inhibitors, but probably not as well as methotrexate, according to a European study of 140 axial spondyloarthritis patients.

“The effect of sulfasalazine on the development of antidrug antibodies has not been studied before. Our initial hypothesis was that methotrexate would [reduce] antibody formation” because it’s been shown to do that before, but that “sulfasalazine would not. This was a surprise to us,” said senior investigator Dr. Alejandro Balsa, chief of rheumatology at La Paz University Hospital in Madrid.

©sshepard/iStock

The findings suggest that sulfasalazine, like methotrexate, might “prevent immunogenicity and, hence ... secondary failure of” a tumor necrosis factor inhibitor (TNFi), he said at the annual meeting of the American College of Rheumatology.

Thirty-one patients (22%) were on infliximab (Remicade) and 109 (78%) were on adalimumab (Humira) in the year-long study, which was conducted in Madrid and Amsterdam.

Of the 90 patients on TNFi monotherapy, 33 (37%) developed TNFi antibodies, including 3 of 13 (23%) on infliximab monotherapy and 30 of 77 (39%) on adalimumab alone. The difference was not statistically significant.

Of the 50 patients on concomitant therapy, antibodies against anti-TNF agents occurred in 6 of 35 on sulfasalazine (17%), including three cases on infliximab and three on adalimumab. There was just one antibody case in 15 patients on methotrexate (7%); the patient was on adalimumab.

The trend toward better antibody protection with methotrexate was, again, not significant, probably because of the small numbers in the study.

Methotrexate and sulfasalazine are not routinely prescribed for axial spondyloarthritis; patients were on them in the study to help with peripheral manifestations. The drugs only prevent antibodies if started before a TNFi. “Once patients develop anti-[TNF] antibodies,” it’s too late, Dr. Balsa noted.

Despite the promising results, he said there’s not enough data at this point to recommend routine pretreatment with methotrexate or sulfasalazine to prevent TNFi antibodies.

As expected, antibodies diminished the clinical effect of a TNFi. Less than a quarter of antibody patients, versus more than a half free from antibodies, reached the investigators’ mark for low disease activity at 1 year: clinical improvement plus a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score below 4 and normal C-reactive protein (P = .03).

Also at 1 year, patients on monotherapy had an overall BASDAI improvement of about 1 point on the 10-point scale. Patients on methotrexate gained an additional point or so (P = .04), while those on sulfasalazine gained about a half point extra (P = .16).

“We only saw significant improvements in patients treated with methotrexate, probably because 100% cotreated with methotrexate had free” serum TNFi “at 1 year, as compared with only 82% cotreated with sulfasalazine,” Dr. Balsa said.

Oddly, the investigators detected free serum TNFi at 1 year in 78 (87%) monotherapy patients, which was more than in those cotreated with sulfasalazine; he didn’t address the finding.

The mean BASDAI at baseline was 6. Ankylosing spondylitis was the most common diagnosis in the study. More than half the subjects were men, the majority of patients were HLA-B27 positive, and their mean disease duration was 11 years.

Dr. Balsa’s institution receives research funding from Pfizer, UCB, and Roche, and he receives speakers fees from those companies plus AbbVie, Merck, and Bristol-Myers Squibb. Other investigators disclosed financial ties to those or other companies.

[email protected]

SAN FRANCISCO – Sulfasalazine prevents formation of antibodies against tumor necrosis factor inhibitors, but probably not as well as methotrexate, according to a European study of 140 axial spondyloarthritis patients.

“The effect of sulfasalazine on the development of antidrug antibodies has not been studied before. Our initial hypothesis was that methotrexate would [reduce] antibody formation” because it’s been shown to do that before, but that “sulfasalazine would not. This was a surprise to us,” said senior investigator Dr. Alejandro Balsa, chief of rheumatology at La Paz University Hospital in Madrid.

©sshepard/iStock

The findings suggest that sulfasalazine, like methotrexate, might “prevent immunogenicity and, hence ... secondary failure of” a tumor necrosis factor inhibitor (TNFi), he said at the annual meeting of the American College of Rheumatology.

Thirty-one patients (22%) were on infliximab (Remicade) and 109 (78%) were on adalimumab (Humira) in the year-long study, which was conducted in Madrid and Amsterdam.

Of the 90 patients on TNFi monotherapy, 33 (37%) developed TNFi antibodies, including 3 of 13 (23%) on infliximab monotherapy and 30 of 77 (39%) on adalimumab alone. The difference was not statistically significant.

Of the 50 patients on concomitant therapy, antibodies against anti-TNF agents occurred in 6 of 35 on sulfasalazine (17%), including three cases on infliximab and three on adalimumab. There was just one antibody case in 15 patients on methotrexate (7%); the patient was on adalimumab.

The trend toward better antibody protection with methotrexate was, again, not significant, probably because of the small numbers in the study.

Methotrexate and sulfasalazine are not routinely prescribed for axial spondyloarthritis; patients were on them in the study to help with peripheral manifestations. The drugs only prevent antibodies if started before a TNFi. “Once patients develop anti-[TNF] antibodies,” it’s too late, Dr. Balsa noted.

Despite the promising results, he said there’s not enough data at this point to recommend routine pretreatment with methotrexate or sulfasalazine to prevent TNFi antibodies.

As expected, antibodies diminished the clinical effect of a TNFi. Less than a quarter of antibody patients, versus more than a half free from antibodies, reached the investigators’ mark for low disease activity at 1 year: clinical improvement plus a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score below 4 and normal C-reactive protein (P = .03).

Also at 1 year, patients on monotherapy had an overall BASDAI improvement of about 1 point on the 10-point scale. Patients on methotrexate gained an additional point or so (P = .04), while those on sulfasalazine gained about a half point extra (P = .16).

“We only saw significant improvements in patients treated with methotrexate, probably because 100% cotreated with methotrexate had free” serum TNFi “at 1 year, as compared with only 82% cotreated with sulfasalazine,” Dr. Balsa said.

Oddly, the investigators detected free serum TNFi at 1 year in 78 (87%) monotherapy patients, which was more than in those cotreated with sulfasalazine; he didn’t address the finding.

The mean BASDAI at baseline was 6. Ankylosing spondylitis was the most common diagnosis in the study. More than half the subjects were men, the majority of patients were HLA-B27 positive, and their mean disease duration was 11 years.

Dr. Balsa’s institution receives research funding from Pfizer, UCB, and Roche, and he receives speakers fees from those companies plus AbbVie, Merck, and Bristol-Myers Squibb. Other investigators disclosed financial ties to those or other companies.

[email protected]

SAN FRANCISCO – The most common fear of rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) patients is that their future suffering will be as bad as their past suffering, according to a French survey of 474 patients.

Overall, 182 of the 303 RA patients (60%) and 122 of the 171 axSpA patients (71%) in the study ranked that fear as at least a 7 on a 10-point scale, and it remained a serious and common concern even among the roughly half of patients who were in remission.

Majorities in both groups were highly concerned about deformity, wheel chair dependence, burdening loved ones, losing autonomy, and disease spread to other joints. Less common fears, but still ranked at least a 7 by about one-third to well over half of patients, were more frequent flares, inability to care for others, losing friends, loss of treatment effectiveness, fear of treatment side effects, and not finding help if independence is lost.

In general, axSpA was perceived as the more frightening disease, with patients more likely than those with RA to give fears presented on the survey a score of 7 or higher; axSpA patients also were more likely to fear the impact of disease on pregnancy and work, and more worried about passing disease onto their children. Fears about joints seizing up, bone and spine fusion, and increased flare activity were far more prevalent in the axSpA group.

The findings are from a test run of a new questionnaire being developed in France to capture the psychological burden of chronic inflammatory disease. The idea is to make patients’ fears and convictions explicit so that providers know what they are and can help patients cope.

“We’ve had this idea for a long time. Patients have fears and beliefs that” are difficult to express, and they get in the way of effective office communication. The questionnaire might break down the walls, so “patients know their doctors understand and are concerned” about their overall well-being, said senior investigator Dr. Francis Berenbaum, chief of rheumatology at Saint Antoine Hospital in Paris.

It’s hoped that the efforts will improve trust and dialogue between patients and doctors and lead to better treatment adherence and follow-up, more effective counseling, and perhaps even new patient-related outcomes for clinical trials, he said at the annual meeting of the American College of Rheumatology.

To create the survey, the team conducted semi-structured patient interviews at rheumatology practices across France. They whittled the responses down to identify 23 common fears and 19 disease-related beliefs in RA and axSpA. The resulting 44-item survey – there are two additional items about pregnancy and work-related concerns – asks patients to rate each one on a scale of 1-10. The team hopes to have data soon to show whether or not the efforts improve outcomes.

Common beliefs in both groups were that fatigue, over-exertion, stress, and weather changes trigger flares, but that moderate physical activity reduces them.

Almost half of RA patients, versus about a quarter of axSpA patients, believed that their disease was triggered by an emotional shock or stressful event, and small minorities in both groups attributed their disease to pollution, vaccines, or passive or active smoking. About 70% of patients in both groups were on biologics, and about one-third in each were very worried that their treatments would cause cancer.

Some “disease perceptions may not be accurate” and “provide a basis for discussion … to dispel misconceptions, align treatment expectations, and provide reassurance,” the investigators noted,

The RA patients were 60 years old on average, and about three-quarters were women. The median disease duration was 10 years, and mean Disease Activity Score (DAS28) was 2.7; axSpA patients were a mean age of 47 years, 43% were women, and the median disease duration was 12 years. Their mean Bath Ankylosing Spondylitis Disease Activity Index score was 3.2.

Foundation Arthritis Jacques Courtin and UCB Pharma funded the work. Dr. Berenbaum has no relevant disclosures. Two investigators are UCB employees.

[email protected]

SAN FRANCISCO – The most common fear of rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) patients is that their future suffering will be as bad as their past suffering, according to a French survey of 474 patients.

Overall, 182 of the 303 RA patients (60%) and 122 of the 171 axSpA patients (71%) in the study ranked that fear as at least a 7 on a 10-point scale, and it remained a serious and common concern even among the roughly half of patients who were in remission.

Majorities in both groups were highly concerned about deformity, wheel chair dependence, burdening loved ones, losing autonomy, and disease spread to other joints. Less common fears, but still ranked at least a 7 by about one-third to well over half of patients, were more frequent flares, inability to care for others, losing friends, loss of treatment effectiveness, fear of treatment side effects, and not finding help if independence is lost.

In general, axSpA was perceived as the more frightening disease, with patients more likely than those with RA to give fears presented on the survey a score of 7 or higher; axSpA patients also were more likely to fear the impact of disease on pregnancy and work, and more worried about passing disease onto their children. Fears about joints seizing up, bone and spine fusion, and increased flare activity were far more prevalent in the axSpA group.

The findings are from a test run of a new questionnaire being developed in France to capture the psychological burden of chronic inflammatory disease. The idea is to make patients’ fears and convictions explicit so that providers know what they are and can help patients cope.

“We’ve had this idea for a long time. Patients have fears and beliefs that” are difficult to express, and they get in the way of effective office communication. The questionnaire might break down the walls, so “patients know their doctors understand and are concerned” about their overall well-being, said senior investigator Dr. Francis Berenbaum, chief of rheumatology at Saint Antoine Hospital in Paris.

It’s hoped that the efforts will improve trust and dialogue between patients and doctors and lead to better treatment adherence and follow-up, more effective counseling, and perhaps even new patient-related outcomes for clinical trials, he said at the annual meeting of the American College of Rheumatology.

To create the survey, the team conducted semi-structured patient interviews at rheumatology practices across France. They whittled the responses down to identify 23 common fears and 19 disease-related beliefs in RA and axSpA. The resulting 44-item survey – there are two additional items about pregnancy and work-related concerns – asks patients to rate each one on a scale of 1-10. The team hopes to have data soon to show whether or not the efforts improve outcomes.

Common beliefs in both groups were that fatigue, over-exertion, stress, and weather changes trigger flares, but that moderate physical activity reduces them.

Almost half of RA patients, versus about a quarter of axSpA patients, believed that their disease was triggered by an emotional shock or stressful event, and small minorities in both groups attributed their disease to pollution, vaccines, or passive or active smoking. About 70% of patients in both groups were on biologics, and about one-third in each were very worried that their treatments would cause cancer.

Some “disease perceptions may not be accurate” and “provide a basis for discussion … to dispel misconceptions, align treatment expectations, and provide reassurance,” the investigators noted,

The RA patients were 60 years old on average, and about three-quarters were women. The median disease duration was 10 years, and mean Disease Activity Score (DAS28) was 2.7; axSpA patients were a mean age of 47 years, 43% were women, and the median disease duration was 12 years. Their mean Bath Ankylosing Spondylitis Disease Activity Index score was 3.2.

Foundation Arthritis Jacques Courtin and UCB Pharma funded the work. Dr. Berenbaum has no relevant disclosures. Two investigators are UCB employees.

[email protected]

SAN FRANCISCO – The most common fear of rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) patients is that their future suffering will be as bad as their past suffering, according to a French survey of 474 patients.

Overall, 182 of the 303 RA patients (60%) and 122 of the 171 axSpA patients (71%) in the study ranked that fear as at least a 7 on a 10-point scale, and it remained a serious and common concern even among the roughly half of patients who were in remission.

Majorities in both groups were highly concerned about deformity, wheel chair dependence, burdening loved ones, losing autonomy, and disease spread to other joints. Less common fears, but still ranked at least a 7 by about one-third to well over half of patients, were more frequent flares, inability to care for others, losing friends, loss of treatment effectiveness, fear of treatment side effects, and not finding help if independence is lost.

In general, axSpA was perceived as the more frightening disease, with patients more likely than those with RA to give fears presented on the survey a score of 7 or higher; axSpA patients also were more likely to fear the impact of disease on pregnancy and work, and more worried about passing disease onto their children. Fears about joints seizing up, bone and spine fusion, and increased flare activity were far more prevalent in the axSpA group.

The findings are from a test run of a new questionnaire being developed in France to capture the psychological burden of chronic inflammatory disease. The idea is to make patients’ fears and convictions explicit so that providers know what they are and can help patients cope.

“We’ve had this idea for a long time. Patients have fears and beliefs that” are difficult to express, and they get in the way of effective office communication. The questionnaire might break down the walls, so “patients know their doctors understand and are concerned” about their overall well-being, said senior investigator Dr. Francis Berenbaum, chief of rheumatology at Saint Antoine Hospital in Paris.

It’s hoped that the efforts will improve trust and dialogue between patients and doctors and lead to better treatment adherence and follow-up, more effective counseling, and perhaps even new patient-related outcomes for clinical trials, he said at the annual meeting of the American College of Rheumatology.

To create the survey, the team conducted semi-structured patient interviews at rheumatology practices across France. They whittled the responses down to identify 23 common fears and 19 disease-related beliefs in RA and axSpA. The resulting 44-item survey – there are two additional items about pregnancy and work-related concerns – asks patients to rate each one on a scale of 1-10. The team hopes to have data soon to show whether or not the efforts improve outcomes.

Common beliefs in both groups were that fatigue, over-exertion, stress, and weather changes trigger flares, but that moderate physical activity reduces them.

Almost half of RA patients, versus about a quarter of axSpA patients, believed that their disease was triggered by an emotional shock or stressful event, and small minorities in both groups attributed their disease to pollution, vaccines, or passive or active smoking. About 70% of patients in both groups were on biologics, and about one-third in each were very worried that their treatments would cause cancer.

Some “disease perceptions may not be accurate” and “provide a basis for discussion … to dispel misconceptions, align treatment expectations, and provide reassurance,” the investigators noted,

The RA patients were 60 years old on average, and about three-quarters were women. The median disease duration was 10 years, and mean Disease Activity Score (DAS28) was 2.7; axSpA patients were a mean age of 47 years, 43% were women, and the median disease duration was 12 years. Their mean Bath Ankylosing Spondylitis Disease Activity Index score was 3.2.

Foundation Arthritis Jacques Courtin and UCB Pharma funded the work. Dr. Berenbaum has no relevant disclosures. Two investigators are UCB employees.

[email protected]

SAN FRANCISCO – Etanercept during pregnancy more than doubled the risk of major congenital malformations in a study by the Organization of Teratology Information Specialists.

The group keeps a prospective registry on exposures to biologics during pregnancy. It is finishing up its adalimumab (Humira) investigation and hasn’t found much to worry about, and continues to gather data on abatacept (Orencia), tocilizumab (Actemra), tofacitinib (Xeljanz), apremilast (Otezla), and certolizumab pegol (Cimzia).

Etanercept (Enbrel), however, seems to be a different story; major malformations turned up in the group’s recently completed investigation. Even so, Organization of Teratology Information Specialists (OTIS) investigator Dr. Christina D. Chambers, Ph.D., of the University of California, San Diego, was careful to note at the annual meeting of the American College of Rheumatology that “etanercept is not meeting the criteria for causality. There’s no pattern” in major defects and “no biological plausibility” because the drug doesn’t seem to cross the placenta when the fetus is most vulnerable to adverse outcomes.

“It is difficult to draw the conclusion that this drug is causing harm. With true teratogens, you tend to see reduced birth weights and an increased risk of spontaneous abortion, which is not the case with etanercept. We are seeing only this one finding that kind of stands alone, and everything else looks pretty good,” she said.

The etanercept study investigated pregnancy outcomes in 370 women exposed to the drug while pregnant, mostly women with rheumatoid arthritis, but also women with psoriasis and ankylosing spondylitis. Their outcomes were compared with 164 pregnant women with the same diseases but no etanercept exposure – the disease control group – and 296 healthy pregnant women.

Women in all three groups were about 33 years old on average, and about 80% were white. The women were enrolled toward the end of their first trimester. Disease severity, comorbidities, and use of vitamins, alcohol, and tobacco were similar between etanercept and disease control women. About 40% of the etanercept and disease control women, but just one in the healthy pregnancy group, were exposed to systemic corticosteroids while pregnant.

There were 33 major structural defects in children born to women taking etanercept versus 7 in the disease control group. That translated to a more than doubling of risk with etanercept (odds ratio, 2.37; 95% confidence interval, 1.02-5.52), and a more than doubling of risk versus the 10 major structural defects in children born to healthy control women (OR, 2.91; 95% CI, 1.37-6.76).

A subanalysis excluded chromosomal anomalies, but “did not [change] our conclusions,” Dr. Chambers said.

Major structural defects generally refer to problems that need a surgical fix, including spina bifida, atrial septal defects, cleft palates, hypospadias, polydactyly, and craniosynostosis.

Minor defects that don’t need surgery, like a missing earlobe, occurred in six children exposed to etanercept and showed two different patterns that involved “three specific minor malformations” not seen in either of the control groups, Dr. Chambers said. She did not elaborate on what those patterns were, but noted that the parents usually had them, too, “suggesting a genetic component as opposed to a drug effect.”

Children in the three study groups had no statistically significant differences in 1-year malignancy rates, serious infections, and hospitalizations, even when exposed to etanercept in the third trimester.

Children exposed to etanercept, however, were more likely to be born preterm and more likely to be small for gestational age in weight, length, and head circumference. They were also more likely than disease control children to screen positive for developmental issues at 1 year, but none of those differences were statistically significant.

Dr. Chambers disclosed funding from 14 companies, including Amgen, the maker of etanercept, and Janssen, Pfizer, Roche, Sanofi/Genzyme, GlaxoSmithKline, and AbbVie, the maker of adalimumab.

[email protected]

SAN FRANCISCO – Etanercept during pregnancy more than doubled the risk of major congenital malformations in a study by the Organization of Teratology Information Specialists.

The group keeps a prospective registry on exposures to biologics during pregnancy. It is finishing up its adalimumab (Humira) investigation and hasn’t found much to worry about, and continues to gather data on abatacept (Orencia), tocilizumab (Actemra), tofacitinib (Xeljanz), apremilast (Otezla), and certolizumab pegol (Cimzia).

Etanercept (Enbrel), however, seems to be a different story; major malformations turned up in the group’s recently completed investigation. Even so, Organization of Teratology Information Specialists (OTIS) investigator Dr. Christina D. Chambers, Ph.D., of the University of California, San Diego, was careful to note at the annual meeting of the American College of Rheumatology that “etanercept is not meeting the criteria for causality. There’s no pattern” in major defects and “no biological plausibility” because the drug doesn’t seem to cross the placenta when the fetus is most vulnerable to adverse outcomes.

“It is difficult to draw the conclusion that this drug is causing harm. With true teratogens, you tend to see reduced birth weights and an increased risk of spontaneous abortion, which is not the case with etanercept. We are seeing only this one finding that kind of stands alone, and everything else looks pretty good,” she said.

The etanercept study investigated pregnancy outcomes in 370 women exposed to the drug while pregnant, mostly women with rheumatoid arthritis, but also women with psoriasis and ankylosing spondylitis. Their outcomes were compared with 164 pregnant women with the same diseases but no etanercept exposure – the disease control group – and 296 healthy pregnant women.

Women in all three groups were about 33 years old on average, and about 80% were white. The women were enrolled toward the end of their first trimester. Disease severity, comorbidities, and use of vitamins, alcohol, and tobacco were similar between etanercept and disease control women. About 40% of the etanercept and disease control women, but just one in the healthy pregnancy group, were exposed to systemic corticosteroids while pregnant.

There were 33 major structural defects in children born to women taking etanercept versus 7 in the disease control group. That translated to a more than doubling of risk with etanercept (odds ratio, 2.37; 95% confidence interval, 1.02-5.52), and a more than doubling of risk versus the 10 major structural defects in children born to healthy control women (OR, 2.91; 95% CI, 1.37-6.76).

A subanalysis excluded chromosomal anomalies, but “did not [change] our conclusions,” Dr. Chambers said.

Major structural defects generally refer to problems that need a surgical fix, including spina bifida, atrial septal defects, cleft palates, hypospadias, polydactyly, and craniosynostosis.

Minor defects that don’t need surgery, like a missing earlobe, occurred in six children exposed to etanercept and showed two different patterns that involved “three specific minor malformations” not seen in either of the control groups, Dr. Chambers said. She did not elaborate on what those patterns were, but noted that the parents usually had them, too, “suggesting a genetic component as opposed to a drug effect.”

Children in the three study groups had no statistically significant differences in 1-year malignancy rates, serious infections, and hospitalizations, even when exposed to etanercept in the third trimester.

Children exposed to etanercept, however, were more likely to be born preterm and more likely to be small for gestational age in weight, length, and head circumference. They were also more likely than disease control children to screen positive for developmental issues at 1 year, but none of those differences were statistically significant.

Dr. Chambers disclosed funding from 14 companies, including Amgen, the maker of etanercept, and Janssen, Pfizer, Roche, Sanofi/Genzyme, GlaxoSmithKline, and AbbVie, the maker of adalimumab.

[email protected]

SAN FRANCISCO – Etanercept during pregnancy more than doubled the risk of major congenital malformations in a study by the Organization of Teratology Information Specialists.

The group keeps a prospective registry on exposures to biologics during pregnancy. It is finishing up its adalimumab (Humira) investigation and hasn’t found much to worry about, and continues to gather data on abatacept (Orencia), tocilizumab (Actemra), tofacitinib (Xeljanz), apremilast (Otezla), and certolizumab pegol (Cimzia).

Etanercept (Enbrel), however, seems to be a different story; major malformations turned up in the group’s recently completed investigation. Even so, Organization of Teratology Information Specialists (OTIS) investigator Dr. Christina D. Chambers, Ph.D., of the University of California, San Diego, was careful to note at the annual meeting of the American College of Rheumatology that “etanercept is not meeting the criteria for causality. There’s no pattern” in major defects and “no biological plausibility” because the drug doesn’t seem to cross the placenta when the fetus is most vulnerable to adverse outcomes.

“It is difficult to draw the conclusion that this drug is causing harm. With true teratogens, you tend to see reduced birth weights and an increased risk of spontaneous abortion, which is not the case with etanercept. We are seeing only this one finding that kind of stands alone, and everything else looks pretty good,” she said.

The etanercept study investigated pregnancy outcomes in 370 women exposed to the drug while pregnant, mostly women with rheumatoid arthritis, but also women with psoriasis and ankylosing spondylitis. Their outcomes were compared with 164 pregnant women with the same diseases but no etanercept exposure – the disease control group – and 296 healthy pregnant women.

Women in all three groups were about 33 years old on average, and about 80% were white. The women were enrolled toward the end of their first trimester. Disease severity, comorbidities, and use of vitamins, alcohol, and tobacco were similar between etanercept and disease control women. About 40% of the etanercept and disease control women, but just one in the healthy pregnancy group, were exposed to systemic corticosteroids while pregnant.

There were 33 major structural defects in children born to women taking etanercept versus 7 in the disease control group. That translated to a more than doubling of risk with etanercept (odds ratio, 2.37; 95% confidence interval, 1.02-5.52), and a more than doubling of risk versus the 10 major structural defects in children born to healthy control women (OR, 2.91; 95% CI, 1.37-6.76).

A subanalysis excluded chromosomal anomalies, but “did not [change] our conclusions,” Dr. Chambers said.

Major structural defects generally refer to problems that need a surgical fix, including spina bifida, atrial septal defects, cleft palates, hypospadias, polydactyly, and craniosynostosis.

Minor defects that don’t need surgery, like a missing earlobe, occurred in six children exposed to etanercept and showed two different patterns that involved “three specific minor malformations” not seen in either of the control groups, Dr. Chambers said. She did not elaborate on what those patterns were, but noted that the parents usually had them, too, “suggesting a genetic component as opposed to a drug effect.”

Children in the three study groups had no statistically significant differences in 1-year malignancy rates, serious infections, and hospitalizations, even when exposed to etanercept in the third trimester.

Children exposed to etanercept, however, were more likely to be born preterm and more likely to be small for gestational age in weight, length, and head circumference. They were also more likely than disease control children to screen positive for developmental issues at 1 year, but none of those differences were statistically significant.

Dr. Chambers disclosed funding from 14 companies, including Amgen, the maker of etanercept, and Janssen, Pfizer, Roche, Sanofi/Genzyme, GlaxoSmithKline, and AbbVie, the maker of adalimumab.

[email protected]

Secukinumab, an interleukin 17-A inhibitor approved for the treatment of moderate to severe psoriasis, significantly reduced the signs and symptoms of ankylosing spondylitis in two phase III trials, researchers reported Dec. 23 in the New England Journal of Medicine.

The results of the double-blind MEASURE 1 and MEASURE 2 trials extend the positive results of the phase II study, according to Dr. Dominique Baeten of the Academic Medical Center at the University of Amsterdam and his colleagues (N Engl J Med. 2015 Dec 23. doi: 10.1056/NEJMoa1505066).

“Although head-to-head trials would be required to fully assess the efficacy and safety of secukinumab versus TNF-inhibitors, the [20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria] response rates achieved with secukinumab at week 16 in our studies were similar to those reported in phase III studies of anti-TNF agents in which most of the patients had not received previous anti-TNF therapy (response rates of 58% to 64% at weeks 12 to 24), even though 30% to 40% of the patients in our studies had had no response to previous anti-TNF treatment,” the authors wrote.

“Thus, secukinumab not only is effective in patients who have not received TNF agents previously but also may be effective in patients in whom previous anti-TNF treatment failed,” they added.

In MEASURE 1, 371 patients received intravenous secukinumab (10 mg/kg of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8.

The study’s primary endpoint of ASAS20 response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively, (P less than .001 for both comparisons with placebo).

In MEASURE 2, 219 patients received subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline; at weeks 1, 2, and 3; and every 4 weeks starting at week 4.

At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg.

In this trial, ASAS20 rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P less than .001 for the 150-mg dose and P = .10 for the 75-mg dose).

The researchers noted that the ineffectiveness of the 75-mg dose in MEASURE 2 suggests that the efficacy of secukinumab at the 75-mg dose in MEASURE 1 may have been due to the greater exposure at week 16 as a result of the intravenous loading regimen, not to the 75-mg subcutaneous maintenance dose.

The safety profile of secukinumab in the present studies was consistent with previous studies of secukinumab for ankylosing spondylitis and moderate-to-severe plaque psoriasis, Dr. Baeten and his associates said.

During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn’s disease were 0.7, 0.9, and 0.7 cases per 100 patient-years, respectively, in secukinumab-treated patients.

Overall, the results suggest that interleukin-17A plays a role in the pathogenesis of ankylosing spondylitis, and they validate inhibition of this cytokine as a potential therapeutic approach, the study authors concluded.

The study was sponsored by Novartis Pharma. Dr. Baeten has received a grant from Novartis to study the impact of IL-17A blockade in experimental models of spondyloarthritis. He also has been a consultant for Novartis for the design and conduct of the secukinumab program in ankylosing spondylitis and psoriatic arthritis.

Secukinumab, an interleukin 17-A inhibitor approved for the treatment of moderate to severe psoriasis, significantly reduced the signs and symptoms of ankylosing spondylitis in two phase III trials, researchers reported Dec. 23 in the New England Journal of Medicine.

The results of the double-blind MEASURE 1 and MEASURE 2 trials extend the positive results of the phase II study, according to Dr. Dominique Baeten of the Academic Medical Center at the University of Amsterdam and his colleagues (N Engl J Med. 2015 Dec 23. doi: 10.1056/NEJMoa1505066).

“Although head-to-head trials would be required to fully assess the efficacy and safety of secukinumab versus TNF-inhibitors, the [20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria] response rates achieved with secukinumab at week 16 in our studies were similar to those reported in phase III studies of anti-TNF agents in which most of the patients had not received previous anti-TNF therapy (response rates of 58% to 64% at weeks 12 to 24), even though 30% to 40% of the patients in our studies had had no response to previous anti-TNF treatment,” the authors wrote.

“Thus, secukinumab not only is effective in patients who have not received TNF agents previously but also may be effective in patients in whom previous anti-TNF treatment failed,” they added.

In MEASURE 1, 371 patients received intravenous secukinumab (10 mg/kg of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8.

The study’s primary endpoint of ASAS20 response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively, (P less than .001 for both comparisons with placebo).

In MEASURE 2, 219 patients received subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline; at weeks 1, 2, and 3; and every 4 weeks starting at week 4.

At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg.

In this trial, ASAS20 rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P less than .001 for the 150-mg dose and P = .10 for the 75-mg dose).

The researchers noted that the ineffectiveness of the 75-mg dose in MEASURE 2 suggests that the efficacy of secukinumab at the 75-mg dose in MEASURE 1 may have been due to the greater exposure at week 16 as a result of the intravenous loading regimen, not to the 75-mg subcutaneous maintenance dose.

The safety profile of secukinumab in the present studies was consistent with previous studies of secukinumab for ankylosing spondylitis and moderate-to-severe plaque psoriasis, Dr. Baeten and his associates said.

During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn’s disease were 0.7, 0.9, and 0.7 cases per 100 patient-years, respectively, in secukinumab-treated patients.

Overall, the results suggest that interleukin-17A plays a role in the pathogenesis of ankylosing spondylitis, and they validate inhibition of this cytokine as a potential therapeutic approach, the study authors concluded.

The study was sponsored by Novartis Pharma. Dr. Baeten has received a grant from Novartis to study the impact of IL-17A blockade in experimental models of spondyloarthritis. He also has been a consultant for Novartis for the design and conduct of the secukinumab program in ankylosing spondylitis and psoriatic arthritis.

Secukinumab, an interleukin 17-A inhibitor approved for the treatment of moderate to severe psoriasis, significantly reduced the signs and symptoms of ankylosing spondylitis in two phase III trials, researchers reported Dec. 23 in the New England Journal of Medicine.

The results of the double-blind MEASURE 1 and MEASURE 2 trials extend the positive results of the phase II study, according to Dr. Dominique Baeten of the Academic Medical Center at the University of Amsterdam and his colleagues (N Engl J Med. 2015 Dec 23. doi: 10.1056/NEJMoa1505066).

“Although head-to-head trials would be required to fully assess the efficacy and safety of secukinumab versus TNF-inhibitors, the [20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria] response rates achieved with secukinumab at week 16 in our studies were similar to those reported in phase III studies of anti-TNF agents in which most of the patients had not received previous anti-TNF therapy (response rates of 58% to 64% at weeks 12 to 24), even though 30% to 40% of the patients in our studies had had no response to previous anti-TNF treatment,” the authors wrote.

“Thus, secukinumab not only is effective in patients who have not received TNF agents previously but also may be effective in patients in whom previous anti-TNF treatment failed,” they added.

In MEASURE 1, 371 patients received intravenous secukinumab (10 mg/kg of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8.

The study’s primary endpoint of ASAS20 response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively, (P less than .001 for both comparisons with placebo).

In MEASURE 2, 219 patients received subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline; at weeks 1, 2, and 3; and every 4 weeks starting at week 4.

At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg.

In this trial, ASAS20 rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P less than .001 for the 150-mg dose and P = .10 for the 75-mg dose).

The researchers noted that the ineffectiveness of the 75-mg dose in MEASURE 2 suggests that the efficacy of secukinumab at the 75-mg dose in MEASURE 1 may have been due to the greater exposure at week 16 as a result of the intravenous loading regimen, not to the 75-mg subcutaneous maintenance dose.

The safety profile of secukinumab in the present studies was consistent with previous studies of secukinumab for ankylosing spondylitis and moderate-to-severe plaque psoriasis, Dr. Baeten and his associates said.

During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn’s disease were 0.7, 0.9, and 0.7 cases per 100 patient-years, respectively, in secukinumab-treated patients.

Overall, the results suggest that interleukin-17A plays a role in the pathogenesis of ankylosing spondylitis, and they validate inhibition of this cytokine as a potential therapeutic approach, the study authors concluded.

The study was sponsored by Novartis Pharma. Dr. Baeten has received a grant from Novartis to study the impact of IL-17A blockade in experimental models of spondyloarthritis. He also has been a consultant for Novartis for the design and conduct of the secukinumab program in ankylosing spondylitis and psoriatic arthritis.