Spondyloarthropathies

The U.S. program to develop biosimilar agents – somewhat akin to generic drugs for complex, biologic molecules that have come off patent protection – is gathering momentum, with the first U.S. biosimilar, Zarxio, approved by the Food and Drug Administration in March 2015 and with the second, a biosimilar to infliximab, recommended by an FDA advisory committee on Feb. 9 of this year.

What’s striking about the burgeoning biosimilar development process, created by the Affordable Care Act, is how it has morphed the FDA from its traditional role as an objective arbiter of a drug’s safety and efficacy into an active partner in shepherding biosimilars onto the market.

As explained on Feb. 4 in testimony before a Congressional committee by Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, the Biologic Price Competition and Innovation Act that was part of the Affordable Care Act launched a new U.S. drug-development pathway expressly for biosimilars. To implement that law, the FDA created an entirely new infrastructure within the agency – the Biosimilar Product Development Program – to help guide prospective manufacturers (called sponsors) of biosimilars through the regulatory and research hurdles to get a new biosimilar approved and into the hands of U.S. patients.

According to Dr. Woodcock, this program involves many steps where FDA staffers provide “review” and “advice” to sponsors on the studies they need to conduct and the analysis they need to perform to get their new products to market. The sponsor joins this program by paying an upfront fee that the FDA uses to keep the program running. Once a sponsor of a prospective biosimilar is in the program, the FDA’s staff helps guide the biosimilar development to a smooth conclusion.

To some extent, the FDA staff fills a similar role for conventional drug-development enterprises, conferring with manufacturers from the outset on matters such as the types and design of studies needed to insure success. What’s different about the biosimilar program is that conventional-drug development went on well before the FDA (or its predecessor) entered the scene, and the U.S. government created the FDA to police and regulate the drug production industry and protect the public against unscrupulous manufacturers of ineffective or dangerous drugs.

In contrast, the FDA itself created this new biosimilar development structure, and Dr. Woodcock noted that the in-depth review and advice meetings that the FDA offers to prospective biosimilar sponsors “has no counterpart in the Prescription Drug User Fee Act program and is unique” to the biosimilar program.

The consequence of having the FDA create the biosimilar development program from the ground up and structure it to provide such intimate input from the agency to sponsors at every step of the way seems to give the agency a notable and somewhat unnerving investment in the program’s success.

Dr. Woodcock called the approval of Zarxio an “exciting accomplishment,” and in her testimony before Congress she trumpeted the fact that as of January 2016 the biosimilar program was working on 59 proposed products that would mimic 18 different reference-product biologics. She also said that the FDA is “excited about the growing demand” for biosimilar-oriented meetings and marketing applications.

Don’t get me wrong: I think that the biosimilar concept is great, and has the potential to make what have become life-changing treatments more affordable and more available. And making the FDA such an active participant in getting biosimilar drugs created and approved is undoubtedly the most efficient way to accomplish this.

But in the process, the biosimilar program has changed the FDA from its more disengaged role as objective pharmaceutical judge into an active and seemingly not completely neutral codeveloper, risking at least the appearance of lost impartiality. Given that the FDA now wears two very different hats, we need to trust that the integrity and dedication of its staff will keep them from confusing their roles as proponent and gatekeeper.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The U.S. program to develop biosimilar agents – somewhat akin to generic drugs for complex, biologic molecules that have come off patent protection – is gathering momentum, with the first U.S. biosimilar, Zarxio, approved by the Food and Drug Administration in March 2015 and with the second, a biosimilar to infliximab, recommended by an FDA advisory committee on Feb. 9 of this year.

What’s striking about the burgeoning biosimilar development process, created by the Affordable Care Act, is how it has morphed the FDA from its traditional role as an objective arbiter of a drug’s safety and efficacy into an active partner in shepherding biosimilars onto the market.

As explained on Feb. 4 in testimony before a Congressional committee by Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, the Biologic Price Competition and Innovation Act that was part of the Affordable Care Act launched a new U.S. drug-development pathway expressly for biosimilars. To implement that law, the FDA created an entirely new infrastructure within the agency – the Biosimilar Product Development Program – to help guide prospective manufacturers (called sponsors) of biosimilars through the regulatory and research hurdles to get a new biosimilar approved and into the hands of U.S. patients.

According to Dr. Woodcock, this program involves many steps where FDA staffers provide “review” and “advice” to sponsors on the studies they need to conduct and the analysis they need to perform to get their new products to market. The sponsor joins this program by paying an upfront fee that the FDA uses to keep the program running. Once a sponsor of a prospective biosimilar is in the program, the FDA’s staff helps guide the biosimilar development to a smooth conclusion.

To some extent, the FDA staff fills a similar role for conventional drug-development enterprises, conferring with manufacturers from the outset on matters such as the types and design of studies needed to insure success. What’s different about the biosimilar program is that conventional-drug development went on well before the FDA (or its predecessor) entered the scene, and the U.S. government created the FDA to police and regulate the drug production industry and protect the public against unscrupulous manufacturers of ineffective or dangerous drugs.

In contrast, the FDA itself created this new biosimilar development structure, and Dr. Woodcock noted that the in-depth review and advice meetings that the FDA offers to prospective biosimilar sponsors “has no counterpart in the Prescription Drug User Fee Act program and is unique” to the biosimilar program.

The consequence of having the FDA create the biosimilar development program from the ground up and structure it to provide such intimate input from the agency to sponsors at every step of the way seems to give the agency a notable and somewhat unnerving investment in the program’s success.

Dr. Woodcock called the approval of Zarxio an “exciting accomplishment,” and in her testimony before Congress she trumpeted the fact that as of January 2016 the biosimilar program was working on 59 proposed products that would mimic 18 different reference-product biologics. She also said that the FDA is “excited about the growing demand” for biosimilar-oriented meetings and marketing applications.

Don’t get me wrong: I think that the biosimilar concept is great, and has the potential to make what have become life-changing treatments more affordable and more available. And making the FDA such an active participant in getting biosimilar drugs created and approved is undoubtedly the most efficient way to accomplish this.

But in the process, the biosimilar program has changed the FDA from its more disengaged role as objective pharmaceutical judge into an active and seemingly not completely neutral codeveloper, risking at least the appearance of lost impartiality. Given that the FDA now wears two very different hats, we need to trust that the integrity and dedication of its staff will keep them from confusing their roles as proponent and gatekeeper.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The U.S. program to develop biosimilar agents – somewhat akin to generic drugs for complex, biologic molecules that have come off patent protection – is gathering momentum, with the first U.S. biosimilar, Zarxio, approved by the Food and Drug Administration in March 2015 and with the second, a biosimilar to infliximab, recommended by an FDA advisory committee on Feb. 9 of this year.

What’s striking about the burgeoning biosimilar development process, created by the Affordable Care Act, is how it has morphed the FDA from its traditional role as an objective arbiter of a drug’s safety and efficacy into an active partner in shepherding biosimilars onto the market.

As explained on Feb. 4 in testimony before a Congressional committee by Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, the Biologic Price Competition and Innovation Act that was part of the Affordable Care Act launched a new U.S. drug-development pathway expressly for biosimilars. To implement that law, the FDA created an entirely new infrastructure within the agency – the Biosimilar Product Development Program – to help guide prospective manufacturers (called sponsors) of biosimilars through the regulatory and research hurdles to get a new biosimilar approved and into the hands of U.S. patients.

According to Dr. Woodcock, this program involves many steps where FDA staffers provide “review” and “advice” to sponsors on the studies they need to conduct and the analysis they need to perform to get their new products to market. The sponsor joins this program by paying an upfront fee that the FDA uses to keep the program running. Once a sponsor of a prospective biosimilar is in the program, the FDA’s staff helps guide the biosimilar development to a smooth conclusion.

To some extent, the FDA staff fills a similar role for conventional drug-development enterprises, conferring with manufacturers from the outset on matters such as the types and design of studies needed to insure success. What’s different about the biosimilar program is that conventional-drug development went on well before the FDA (or its predecessor) entered the scene, and the U.S. government created the FDA to police and regulate the drug production industry and protect the public against unscrupulous manufacturers of ineffective or dangerous drugs.

In contrast, the FDA itself created this new biosimilar development structure, and Dr. Woodcock noted that the in-depth review and advice meetings that the FDA offers to prospective biosimilar sponsors “has no counterpart in the Prescription Drug User Fee Act program and is unique” to the biosimilar program.

The consequence of having the FDA create the biosimilar development program from the ground up and structure it to provide such intimate input from the agency to sponsors at every step of the way seems to give the agency a notable and somewhat unnerving investment in the program’s success.

Dr. Woodcock called the approval of Zarxio an “exciting accomplishment,” and in her testimony before Congress she trumpeted the fact that as of January 2016 the biosimilar program was working on 59 proposed products that would mimic 18 different reference-product biologics. She also said that the FDA is “excited about the growing demand” for biosimilar-oriented meetings and marketing applications.

Don’t get me wrong: I think that the biosimilar concept is great, and has the potential to make what have become life-changing treatments more affordable and more available. And making the FDA such an active participant in getting biosimilar drugs created and approved is undoubtedly the most efficient way to accomplish this.

But in the process, the biosimilar program has changed the FDA from its more disengaged role as objective pharmaceutical judge into an active and seemingly not completely neutral codeveloper, risking at least the appearance of lost impartiality. Given that the FDA now wears two very different hats, we need to trust that the integrity and dedication of its staff will keep them from confusing their roles as proponent and gatekeeper.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The presence of fibromyalgia in patients who are undergoing treatment of spondyloarthritis (SpA) is associated with higher measures of disease activity and shorter duration of first-time treatment with tumor necrosis factor inhibitors, according to results of a study measuring the impact and prevalence of fibromyalgia coexisting with SpA.

The results confirm “that the existence of concomitant FM [fibromyalgia] in SpA might complicate the evaluation of treatment response and [suggest] that coexistence of FM should be carefully screened when initiating a TNFi [tumor necrosis factor inhibitor] and/or evaluating its treatment effect, especially in the presence of peripheral and/or enthesitic symptoms and in the presence of very severe disease activity and patient-reported scores,” wrote Dr. Natalia Bello and her colleagues at Cochin Hospital, Paris (Arthritis Res Ther. 2016 Feb 9;18:42. doi: 10.1186/s13075-016-0943-z).

©Zerbor/Thinkstock

They recruited patients from Cochin Hospital, a tertiary care facility, and its rheumatology department’s outpatient clinic. Rather than use the 1990 American College of Rheumatology (ACR) classification criteria of FM or the 2010 ACR or modified 2010 ACR diagnostic criteria, which were developed for research and classification purposes, the investigators diagnosed FM based on a score of 5 or 6 on the six-question, self-reported Fibromyalgia Rapid Screening Tool (FiRST), which has 90.5% sensitivity and 85.7% specificity for FM. Patients’ SpA diagnoses were made by their rheumatologists. Overall, 30% of the cohort was female and had a mean age of 43 years.

The overall FM prevalence in the cohort was 21.4% (42 of 196 patients) and did not differ significantly according to whether the patients met either the clinical or imaging ASAS (Assessment of Spondyloarthritis International Society) criteria (21.3% vs. 18.8%, respectively) or whether they did or did not fulfill the ASAS criteria (21.1% vs. 30.0%, respectively).

Previous studies have shown the prevalence of FM at 12.6%-15.0% in SpA patients. Classifying axial SpA based on the clinical arm criteria alone has been controversial, the investigators said, mainly because it does not require an objective sign of inflammation (abnormal C-reactive protein or presence of inflammatory lesions seen on MRI of the sacroiliac joint) or structural damage in the sacroiliac joint seen on pelvic radiographs. But at least in this study there was no difference in FM prevalence in regard to whether patients met either the imaging and clinical arms of the ASAS classification criteria for axial SpA or both.

The study, according to the best knowledge of the investigators, is the first “to evaluate the prevalence of FM in a population of patients with SpA with regard to the fulfillment of the ASAS classification criteria.”

FM patients had as expected a significantly higher rate of either history of depression, or use of psychotropic drugs or strong opioids, compared with patients without FM (67% vs. 35%; P less than .01). Rates of exposure to treatment with different drug types (nonsteroidal anti-inflammatory drugs or conventional antirheumatic disease-modifying drugs) did not differ between those with and without FM, but FM patients switched significantly more often from their first TNFi (15.2% vs. 4.0%) and used it for a significantly shorter mean duration (1.7 vs. 3.5 years). The percentage of patients still taking their first TNFi after 2 years also was significantly lower among FM patients (28.1% vs. 41.7%).

Within the entire cohort, FM patients more often had enthesitis (59.5% vs. 39.0%, P  =  .01), a higher total Bath Ankylosing Spondylitis Disease Activity Index (4.7 vs. 2.6; P less than .01), higher global visual analog scale (5.9 vs. 3.0; P less than .01), and higher Bath Ankylosing Spondylitis Functional Index (4.8 vs. 2.0; P less than .01).

The authors suggested that FM patients’ higher rates of peripheral symptoms and enthesitis may warrant the use of the FiRST questionnaire in clinical practice before starting a TNFi in SpA patients to detect potentially coexisting FM.

The authors had no conflicts of interest to declare.

jevans@frontlinemedcom.com

The presence of fibromyalgia in patients who are undergoing treatment of spondyloarthritis (SpA) is associated with higher measures of disease activity and shorter duration of first-time treatment with tumor necrosis factor inhibitors, according to results of a study measuring the impact and prevalence of fibromyalgia coexisting with SpA.

The results confirm “that the existence of concomitant FM [fibromyalgia] in SpA might complicate the evaluation of treatment response and [suggest] that coexistence of FM should be carefully screened when initiating a TNFi [tumor necrosis factor inhibitor] and/or evaluating its treatment effect, especially in the presence of peripheral and/or enthesitic symptoms and in the presence of very severe disease activity and patient-reported scores,” wrote Dr. Natalia Bello and her colleagues at Cochin Hospital, Paris (Arthritis Res Ther. 2016 Feb 9;18:42. doi: 10.1186/s13075-016-0943-z).

©Zerbor/Thinkstock

They recruited patients from Cochin Hospital, a tertiary care facility, and its rheumatology department’s outpatient clinic. Rather than use the 1990 American College of Rheumatology (ACR) classification criteria of FM or the 2010 ACR or modified 2010 ACR diagnostic criteria, which were developed for research and classification purposes, the investigators diagnosed FM based on a score of 5 or 6 on the six-question, self-reported Fibromyalgia Rapid Screening Tool (FiRST), which has 90.5% sensitivity and 85.7% specificity for FM. Patients’ SpA diagnoses were made by their rheumatologists. Overall, 30% of the cohort was female and had a mean age of 43 years.

The overall FM prevalence in the cohort was 21.4% (42 of 196 patients) and did not differ significantly according to whether the patients met either the clinical or imaging ASAS (Assessment of Spondyloarthritis International Society) criteria (21.3% vs. 18.8%, respectively) or whether they did or did not fulfill the ASAS criteria (21.1% vs. 30.0%, respectively).

Previous studies have shown the prevalence of FM at 12.6%-15.0% in SpA patients. Classifying axial SpA based on the clinical arm criteria alone has been controversial, the investigators said, mainly because it does not require an objective sign of inflammation (abnormal C-reactive protein or presence of inflammatory lesions seen on MRI of the sacroiliac joint) or structural damage in the sacroiliac joint seen on pelvic radiographs. But at least in this study there was no difference in FM prevalence in regard to whether patients met either the imaging and clinical arms of the ASAS classification criteria for axial SpA or both.

The study, according to the best knowledge of the investigators, is the first “to evaluate the prevalence of FM in a population of patients with SpA with regard to the fulfillment of the ASAS classification criteria.”

FM patients had as expected a significantly higher rate of either history of depression, or use of psychotropic drugs or strong opioids, compared with patients without FM (67% vs. 35%; P less than .01). Rates of exposure to treatment with different drug types (nonsteroidal anti-inflammatory drugs or conventional antirheumatic disease-modifying drugs) did not differ between those with and without FM, but FM patients switched significantly more often from their first TNFi (15.2% vs. 4.0%) and used it for a significantly shorter mean duration (1.7 vs. 3.5 years). The percentage of patients still taking their first TNFi after 2 years also was significantly lower among FM patients (28.1% vs. 41.7%).

Within the entire cohort, FM patients more often had enthesitis (59.5% vs. 39.0%, P  =  .01), a higher total Bath Ankylosing Spondylitis Disease Activity Index (4.7 vs. 2.6; P less than .01), higher global visual analog scale (5.9 vs. 3.0; P less than .01), and higher Bath Ankylosing Spondylitis Functional Index (4.8 vs. 2.0; P less than .01).

The authors suggested that FM patients’ higher rates of peripheral symptoms and enthesitis may warrant the use of the FiRST questionnaire in clinical practice before starting a TNFi in SpA patients to detect potentially coexisting FM.

The authors had no conflicts of interest to declare.

jevans@frontlinemedcom.com

The presence of fibromyalgia in patients who are undergoing treatment of spondyloarthritis (SpA) is associated with higher measures of disease activity and shorter duration of first-time treatment with tumor necrosis factor inhibitors, according to results of a study measuring the impact and prevalence of fibromyalgia coexisting with SpA.

The results confirm “that the existence of concomitant FM [fibromyalgia] in SpA might complicate the evaluation of treatment response and [suggest] that coexistence of FM should be carefully screened when initiating a TNFi [tumor necrosis factor inhibitor] and/or evaluating its treatment effect, especially in the presence of peripheral and/or enthesitic symptoms and in the presence of very severe disease activity and patient-reported scores,” wrote Dr. Natalia Bello and her colleagues at Cochin Hospital, Paris (Arthritis Res Ther. 2016 Feb 9;18:42. doi: 10.1186/s13075-016-0943-z).

©Zerbor/Thinkstock

They recruited patients from Cochin Hospital, a tertiary care facility, and its rheumatology department’s outpatient clinic. Rather than use the 1990 American College of Rheumatology (ACR) classification criteria of FM or the 2010 ACR or modified 2010 ACR diagnostic criteria, which were developed for research and classification purposes, the investigators diagnosed FM based on a score of 5 or 6 on the six-question, self-reported Fibromyalgia Rapid Screening Tool (FiRST), which has 90.5% sensitivity and 85.7% specificity for FM. Patients’ SpA diagnoses were made by their rheumatologists. Overall, 30% of the cohort was female and had a mean age of 43 years.

The overall FM prevalence in the cohort was 21.4% (42 of 196 patients) and did not differ significantly according to whether the patients met either the clinical or imaging ASAS (Assessment of Spondyloarthritis International Society) criteria (21.3% vs. 18.8%, respectively) or whether they did or did not fulfill the ASAS criteria (21.1% vs. 30.0%, respectively).

Previous studies have shown the prevalence of FM at 12.6%-15.0% in SpA patients. Classifying axial SpA based on the clinical arm criteria alone has been controversial, the investigators said, mainly because it does not require an objective sign of inflammation (abnormal C-reactive protein or presence of inflammatory lesions seen on MRI of the sacroiliac joint) or structural damage in the sacroiliac joint seen on pelvic radiographs. But at least in this study there was no difference in FM prevalence in regard to whether patients met either the imaging and clinical arms of the ASAS classification criteria for axial SpA or both.

The study, according to the best knowledge of the investigators, is the first “to evaluate the prevalence of FM in a population of patients with SpA with regard to the fulfillment of the ASAS classification criteria.”

FM patients had as expected a significantly higher rate of either history of depression, or use of psychotropic drugs or strong opioids, compared with patients without FM (67% vs. 35%; P less than .01). Rates of exposure to treatment with different drug types (nonsteroidal anti-inflammatory drugs or conventional antirheumatic disease-modifying drugs) did not differ between those with and without FM, but FM patients switched significantly more often from their first TNFi (15.2% vs. 4.0%) and used it for a significantly shorter mean duration (1.7 vs. 3.5 years). The percentage of patients still taking their first TNFi after 2 years also was significantly lower among FM patients (28.1% vs. 41.7%).

Within the entire cohort, FM patients more often had enthesitis (59.5% vs. 39.0%, P  =  .01), a higher total Bath Ankylosing Spondylitis Disease Activity Index (4.7 vs. 2.6; P less than .01), higher global visual analog scale (5.9 vs. 3.0; P less than .01), and higher Bath Ankylosing Spondylitis Functional Index (4.8 vs. 2.0; P less than .01).

The authors suggested that FM patients’ higher rates of peripheral symptoms and enthesitis may warrant the use of the FiRST questionnaire in clinical practice before starting a TNFi in SpA patients to detect potentially coexisting FM.

The authors had no conflicts of interest to declare.

jevans@frontlinemedcom.com

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.

mzoler@frontlinemedcom.com

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.

mzoler@frontlinemedcom.com

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.

mzoler@frontlinemedcom.com

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.

jevans@rontlinemedcom.com

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.

jevans@rontlinemedcom.com

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.

jevans@rontlinemedcom.com

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 obnews@frontlinemedcom.com.

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 obnews@frontlinemedcom.com.

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 obnews@frontlinemedcom.com.