Rheumatoid Arthritis

The Food and Drug Administration’s Arthritis Advisory Committee, together with an added complement of dermatologists and gastroenterologists, unanimously recommended during meetings on July 12 and 13 that the agency license a biosimilar Humira (adalimumab) that is made by Amgen and a biosimilar Enbrel (etanercept) that is made by Sandoz for many of the same indications held by the reference drugs.

The FDA advisory panel that endorsed biosimilar Humira recommended the agent’s approval in a 26-0 vote for many, but not all of the indications currently assigned to Humira itself: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis in patients at least 4 years old, plaque psoriasis, adult Crohn’s disease, and adult ulcerative colitis.

A slightly different group of 20 advisory panel members (without any gastroenterologists) voted 20-0 in favor of the FDA granting biosimilar Enbrel all five of the indications now held by Enbrel: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and plaque psoriasis.

The biosimilar Humira and the biosimilar Enbrel are, respectively, the third and fourth candidate biosimilars to emerge from the FDA’s development program and receive advisory committee scrutiny and support. The first agent through the process, biosimilar filgrastim (Zarxio) received FDA approval in 2015 and is available in the United States. Although the second biosimilar through the process, the tumor necrosis factor inhibitor Inflectra that is biosimilar Remicade (infliximab), received FDA approval in April of this year, it has not yet become available for sale, although a spokeswoman for the company that will market it, Pfizer, said that the company expects to start U.S. sales of Inflectra before the end of 2016.

While the Arthritis Advisory Committee ended each of its daylong deliberations for each of the two candidate biosimilars with unanimous support, the panelists’ discussions among themselves and with FDA staffers reflected some uncertainty with the biosimilar concept, especially during the first day when they focused on biosimilar Humira. The major sticking point revolved around the regulatory pathway to approval first established by the Biologics Price Competition and Innovation Act of 2009 and subsequently refined by the FDA that allows a candidate biosimilar to establish its biosimilarity primarily though the results of analytical studies that establish that the candidate molecule is highly similar to the reference molecule. This approval scheme uses clinical trials in a confirmatory role to establish biosimilarity rather than as the linchpin of approval.

It also means that the FDA can grant clinical indications to the biosimilar drug based not on the results from clinical trials, but based entirely on what have already been demonstrated as safe and effective clinical applications for the reference drug. For example, the biosimilar Humira underwent testing in two clinical studies showing similar efficacy and safety as Humira in patients with rheumatoid arthritis and in patients with plaque psoriasis, but received endorsements based on extrapolations for an additional five indications. Biosimilar Enbrel was compared with Enbrel in patients with plaque psoriasis only and still received extrapolated indications for the additional four rheumatologic conditions.

“This is a new level of extrapolation, across indications,” noted Sarah E. Streett, MD, a gastroenterologist at Stanford (Calif.) University, one of several panelists who initially voiced uncertainty about the concept.

But FDA staffer Nikolay P. Nikolov, MD, who led the agency’s presentation, assured the panelists that the concept of extrapolation was at the heart of biosimilar development and regulatory assessment.

“We have confidence from the data that the two molecules [the reference drug and biosimilar drug] are so similar that we can rely on the safety and efficacy of the reference product. The premise of our approach to biosimilars is that this is not a new molecule that we know nothing about.”

The other uncertainty about biosimilar Humira and biosimilar Enbrel that raised concerns of many panelists were the prospects for nonmedical switching once these drugs reach the market. Nonmedical switching refers to when an insurance company or pharmacy benefit manager substitutes a biosimilar for a reference drug without approval from or even the knowledge of the prescribing physician or the patient. Many of the people who spoke during the public forum period on both days of hearings voiced their concerns about this prospect.

“Nonmedical switching is a major concern of clinicians and policy makers, and we need greater clarification from the FDA,” said committee chair Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School in Boston.

“I see a remarkable disconnect between the public’s concerns [about nonmedical switching] and the charge to the committee. These are essential issues that need a forum to be aired out,” said panelist Steven F. Solga, MD, chief of gastroenterology at St. Luke’s Hospital in Bethlehem, Pa.

Dr. Nikolov assured committee members that the FDA recognized this concern and was working on it. “We appreciate the disconnect between the charge and the concerns of the community. I assure you that the issues brought up will be part of our discussions so we can get this [biosimilar pathway] implemented the right way.”

According to the FDA’s regulations, a biosimilar designation does not allow for nonmedical switching, something that could only happen under a related but distinct designation known as interchangeability. During the committee meeting on July 13, a FDA staffer said that the agency is currently developing guidance for an “interchangeable” designation and plans to have it available before then end of 2016.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The Food and Drug Administration’s Arthritis Advisory Committee, together with an added complement of dermatologists and gastroenterologists, unanimously recommended during meetings on July 12 and 13 that the agency license a biosimilar Humira (adalimumab) that is made by Amgen and a biosimilar Enbrel (etanercept) that is made by Sandoz for many of the same indications held by the reference drugs.

The FDA advisory panel that endorsed biosimilar Humira recommended the agent’s approval in a 26-0 vote for many, but not all of the indications currently assigned to Humira itself: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis in patients at least 4 years old, plaque psoriasis, adult Crohn’s disease, and adult ulcerative colitis.

A slightly different group of 20 advisory panel members (without any gastroenterologists) voted 20-0 in favor of the FDA granting biosimilar Enbrel all five of the indications now held by Enbrel: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and plaque psoriasis.

The biosimilar Humira and the biosimilar Enbrel are, respectively, the third and fourth candidate biosimilars to emerge from the FDA’s development program and receive advisory committee scrutiny and support. The first agent through the process, biosimilar filgrastim (Zarxio) received FDA approval in 2015 and is available in the United States. Although the second biosimilar through the process, the tumor necrosis factor inhibitor Inflectra that is biosimilar Remicade (infliximab), received FDA approval in April of this year, it has not yet become available for sale, although a spokeswoman for the company that will market it, Pfizer, said that the company expects to start U.S. sales of Inflectra before the end of 2016.

While the Arthritis Advisory Committee ended each of its daylong deliberations for each of the two candidate biosimilars with unanimous support, the panelists’ discussions among themselves and with FDA staffers reflected some uncertainty with the biosimilar concept, especially during the first day when they focused on biosimilar Humira. The major sticking point revolved around the regulatory pathway to approval first established by the Biologics Price Competition and Innovation Act of 2009 and subsequently refined by the FDA that allows a candidate biosimilar to establish its biosimilarity primarily though the results of analytical studies that establish that the candidate molecule is highly similar to the reference molecule. This approval scheme uses clinical trials in a confirmatory role to establish biosimilarity rather than as the linchpin of approval.

It also means that the FDA can grant clinical indications to the biosimilar drug based not on the results from clinical trials, but based entirely on what have already been demonstrated as safe and effective clinical applications for the reference drug. For example, the biosimilar Humira underwent testing in two clinical studies showing similar efficacy and safety as Humira in patients with rheumatoid arthritis and in patients with plaque psoriasis, but received endorsements based on extrapolations for an additional five indications. Biosimilar Enbrel was compared with Enbrel in patients with plaque psoriasis only and still received extrapolated indications for the additional four rheumatologic conditions.

“This is a new level of extrapolation, across indications,” noted Sarah E. Streett, MD, a gastroenterologist at Stanford (Calif.) University, one of several panelists who initially voiced uncertainty about the concept.

But FDA staffer Nikolay P. Nikolov, MD, who led the agency’s presentation, assured the panelists that the concept of extrapolation was at the heart of biosimilar development and regulatory assessment.

“We have confidence from the data that the two molecules [the reference drug and biosimilar drug] are so similar that we can rely on the safety and efficacy of the reference product. The premise of our approach to biosimilars is that this is not a new molecule that we know nothing about.”

The other uncertainty about biosimilar Humira and biosimilar Enbrel that raised concerns of many panelists were the prospects for nonmedical switching once these drugs reach the market. Nonmedical switching refers to when an insurance company or pharmacy benefit manager substitutes a biosimilar for a reference drug without approval from or even the knowledge of the prescribing physician or the patient. Many of the people who spoke during the public forum period on both days of hearings voiced their concerns about this prospect.

“Nonmedical switching is a major concern of clinicians and policy makers, and we need greater clarification from the FDA,” said committee chair Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School in Boston.

“I see a remarkable disconnect between the public’s concerns [about nonmedical switching] and the charge to the committee. These are essential issues that need a forum to be aired out,” said panelist Steven F. Solga, MD, chief of gastroenterology at St. Luke’s Hospital in Bethlehem, Pa.

Dr. Nikolov assured committee members that the FDA recognized this concern and was working on it. “We appreciate the disconnect between the charge and the concerns of the community. I assure you that the issues brought up will be part of our discussions so we can get this [biosimilar pathway] implemented the right way.”

According to the FDA’s regulations, a biosimilar designation does not allow for nonmedical switching, something that could only happen under a related but distinct designation known as interchangeability. During the committee meeting on July 13, a FDA staffer said that the agency is currently developing guidance for an “interchangeable” designation and plans to have it available before then end of 2016.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The Food and Drug Administration’s Arthritis Advisory Committee, together with an added complement of dermatologists and gastroenterologists, unanimously recommended during meetings on July 12 and 13 that the agency license a biosimilar Humira (adalimumab) that is made by Amgen and a biosimilar Enbrel (etanercept) that is made by Sandoz for many of the same indications held by the reference drugs.

The FDA advisory panel that endorsed biosimilar Humira recommended the agent’s approval in a 26-0 vote for many, but not all of the indications currently assigned to Humira itself: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis in patients at least 4 years old, plaque psoriasis, adult Crohn’s disease, and adult ulcerative colitis.

A slightly different group of 20 advisory panel members (without any gastroenterologists) voted 20-0 in favor of the FDA granting biosimilar Enbrel all five of the indications now held by Enbrel: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and plaque psoriasis.

The biosimilar Humira and the biosimilar Enbrel are, respectively, the third and fourth candidate biosimilars to emerge from the FDA’s development program and receive advisory committee scrutiny and support. The first agent through the process, biosimilar filgrastim (Zarxio) received FDA approval in 2015 and is available in the United States. Although the second biosimilar through the process, the tumor necrosis factor inhibitor Inflectra that is biosimilar Remicade (infliximab), received FDA approval in April of this year, it has not yet become available for sale, although a spokeswoman for the company that will market it, Pfizer, said that the company expects to start U.S. sales of Inflectra before the end of 2016.

While the Arthritis Advisory Committee ended each of its daylong deliberations for each of the two candidate biosimilars with unanimous support, the panelists’ discussions among themselves and with FDA staffers reflected some uncertainty with the biosimilar concept, especially during the first day when they focused on biosimilar Humira. The major sticking point revolved around the regulatory pathway to approval first established by the Biologics Price Competition and Innovation Act of 2009 and subsequently refined by the FDA that allows a candidate biosimilar to establish its biosimilarity primarily though the results of analytical studies that establish that the candidate molecule is highly similar to the reference molecule. This approval scheme uses clinical trials in a confirmatory role to establish biosimilarity rather than as the linchpin of approval.

It also means that the FDA can grant clinical indications to the biosimilar drug based not on the results from clinical trials, but based entirely on what have already been demonstrated as safe and effective clinical applications for the reference drug. For example, the biosimilar Humira underwent testing in two clinical studies showing similar efficacy and safety as Humira in patients with rheumatoid arthritis and in patients with plaque psoriasis, but received endorsements based on extrapolations for an additional five indications. Biosimilar Enbrel was compared with Enbrel in patients with plaque psoriasis only and still received extrapolated indications for the additional four rheumatologic conditions.

“This is a new level of extrapolation, across indications,” noted Sarah E. Streett, MD, a gastroenterologist at Stanford (Calif.) University, one of several panelists who initially voiced uncertainty about the concept.

But FDA staffer Nikolay P. Nikolov, MD, who led the agency’s presentation, assured the panelists that the concept of extrapolation was at the heart of biosimilar development and regulatory assessment.

“We have confidence from the data that the two molecules [the reference drug and biosimilar drug] are so similar that we can rely on the safety and efficacy of the reference product. The premise of our approach to biosimilars is that this is not a new molecule that we know nothing about.”

The other uncertainty about biosimilar Humira and biosimilar Enbrel that raised concerns of many panelists were the prospects for nonmedical switching once these drugs reach the market. Nonmedical switching refers to when an insurance company or pharmacy benefit manager substitutes a biosimilar for a reference drug without approval from or even the knowledge of the prescribing physician or the patient. Many of the people who spoke during the public forum period on both days of hearings voiced their concerns about this prospect.

“Nonmedical switching is a major concern of clinicians and policy makers, and we need greater clarification from the FDA,” said committee chair Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School in Boston.

“I see a remarkable disconnect between the public’s concerns [about nonmedical switching] and the charge to the committee. These are essential issues that need a forum to be aired out,” said panelist Steven F. Solga, MD, chief of gastroenterology at St. Luke’s Hospital in Bethlehem, Pa.

Dr. Nikolov assured committee members that the FDA recognized this concern and was working on it. “We appreciate the disconnect between the charge and the concerns of the community. I assure you that the issues brought up will be part of our discussions so we can get this [biosimilar pathway] implemented the right way.”

According to the FDA’s regulations, a biosimilar designation does not allow for nonmedical switching, something that could only happen under a related but distinct designation known as interchangeability. During the committee meeting on July 13, a FDA staffer said that the agency is currently developing guidance for an “interchangeable” designation and plans to have it available before then end of 2016.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

In a 26-0 vote, the Food and Drug Administration’s arthritis advisory committee recommended July 12 that the agency license an Amgen product as biosimilar to Humira (adalimumab) for seven distinct indications: rheumatoid arthritis, juvenile idiopathic arthritis (in patients at least 4 years old), psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, adult Crohn’s disease, and adult ulcerative colitis.

Developing Story

In a 26-0 vote, the Food and Drug Administration’s arthritis advisory committee recommended July 12 that the agency license an Amgen product as biosimilar to Humira (adalimumab) for seven distinct indications: rheumatoid arthritis, juvenile idiopathic arthritis (in patients at least 4 years old), psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, adult Crohn’s disease, and adult ulcerative colitis.

Developing Story

In a 26-0 vote, the Food and Drug Administration’s arthritis advisory committee recommended July 12 that the agency license an Amgen product as biosimilar to Humira (adalimumab) for seven distinct indications: rheumatoid arthritis, juvenile idiopathic arthritis (in patients at least 4 years old), psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, adult Crohn’s disease, and adult ulcerative colitis.

Developing Story

An implanted vagus nerve stimulator like that used for epilepsy treatment reduced inflammatory markers and significantly improved symptoms and function in a small cohort of patients with rheumatoid arthritis.

After 42 days, almost 30% of patients had achieved disease remission, Frieda A. Koopman, MD, and her colleagues reported in the July issue of the Proceedings of the National Academy of Science (doi: 10.1073/pnas.1605635113). The improvements disappeared rapidly when the devices were turned off, but were quickly reestablished after stimulation resumed.

“This first-in-class study supports a conceptual framework for further studies of electronic medical devices in diseases currently treated with drugs, an approach termed ‘bioelectronic medicine,’” wrote Dr. Koopman of the University of Amsterdam, and her coauthors.

The team built on evidence of what they termed a “reflex neural circuit” in the vagus that strongly influences the production of inflammatory cytokines. Animal studies showed that electrical stimulation of the vagus nerve encouraged choline acetyltransferase–positive T cells to secrete acetylcholine in the spleen and other tissues. Acetylcholine binds to a class of nicotinic receptors on monocytes, macrophages, and stromal cells, and inhibits their inflammatory response.

“Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in experimental models of endotoxemia, sepsis, colitis, and other preclinical animal models of inflammatory syndromes,” the team noted.

The group reported on two human studies, totaling 25 patients. The first comprised seven patients with epilepsy who received the implanted vagus nerve stimulator for medically refractory seizures. None of these patients had a history of RA or any other inflammatory disease. The second group was all patients with active RA.

Each epilepsy patient contributed peripheral blood for study, which was collected before, during and after the implantation surgery. The team studied inflammatory markers by adding endotoxin to the samples. Those collected after the patient had been exposed to a single 30-second stimulation at 20 Hertz showed significantly inhibited production of TNF-alpha, compared with that seen in unexposed blood. Interleukin (IL)-6 and IL-1beta was also inhibited significantly by vagus nerve stimulation.

The next study involved 17 patients who had active RA, but not epilepsy. Of these, seven had failed methotrexate but were naïve to biologics; the rest had failed methotrexate and at least two biologics from different classes. Their average disease duration was 11 years.

The 86-day study gradually titrated the stimulation dose, but even at its highest, stimulation was far less than what is typically employed in epilepsy, “in which current is delivered at 60-second intervals, followed by an off interval of 5-180 minutes, repeated continuously,” the investigators wrote. “Thus, epilepsy patients may receive electrical current delivery for up to 240 minutes daily. Preclinical studies have established that stimulation of the inflammatory reflex for as little as 60 seconds confers significant inhibition of cytokine production for up to 24 hours.”

There was a 14-day post-implantation washout period with no stimulation, followed by 28 days of treatment titration. During that time, stimulation was ramped up from single 60-second stimulation with electric pulses of 250-microseconds duration at 10 Hertz and an output current between 0.25-2.0 milliamps, to the highest amperage tolerated (up to 2.0 milliamps).

That dose was the treatment target, and delivered once daily for 60 seconds in 250-microsecond pulse widths at 10 Hertz. At day 28, patients who had not had good clinical response according to EULAR response criteria, had their stimulation increased to four times daily.

In the group of seven methotrexate-resistant patients, two received electric current pulses four times daily. In the group of 10 methotrexate- and biologic-resistant patients, 6 received the four-dose stimulation.

On day 42, TNF-alpha levels in cultured peripheral blood were significantly reduced from baseline.

At that time, the vagus nerve stimulator was turned off for 14 days. By the end of the silent period, TNF-alpha levels had risen significantly from the day 42 levels. The stimulator was restarted on day 56. By day 84, after 28 more days of stimulation, TNF-alpha levels had again decreased significantly.

Symptoms and function as measured by the Disease Activity Score 28 followed a similar trajectory, improving during the initial treatment, worsening during the period of no stimulation, and improving again when stimulation was restarted. Symptom and function scores correlated positively with change in TNF levels.

The investigators also assessed the response rates according to American College of Rheumatology criteria. At day 42, 71% of those in the methotrexate-resistant group had achieved a 20% response; 57% a 50% response; and 28.6% a 70% response. Response was not as dramatic in the group resistant to both drug classes: rates were 70%, 30%, and 0%.

By day 42, nearly 30% of patients overall achieved remission, which was defined as a DAS28 score of less than 2.6. This constituted improvement in all the score components, including tender joint count, swollen joint count, patient’s assessment of pain, patient’s global assessment, physician’s global assessment, and C-reactive protein.

Finally, the investigators noted decreased levels of most serum cytokines. Most, including serum TNF, IL-10, IL-12p70, IL-13, IL-1alpha, IL-1beta, IL-2, IL-4, IL-5, and TNF-a-beta, were below 1 pg/ml.

Adverse events were common (16 patients) but reported as mild-moderate. The included hoarseness (5), hypoesthesia (4), parasthesia (2), dyspnea (2), and bradycardia (1), among others. There were no implantation-related infections. One patient reported postimplantation pain.

SetPoint Medical, of Valencia, Calif., makes the device and conducted the study. Dr. Koopman made no financial disclosures. However, several of the other authors are employees of Set Point, and of GlaxoSmithKline, which holds equity interest in the company.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

An implanted vagus nerve stimulator like that used for epilepsy treatment reduced inflammatory markers and significantly improved symptoms and function in a small cohort of patients with rheumatoid arthritis.

After 42 days, almost 30% of patients had achieved disease remission, Frieda A. Koopman, MD, and her colleagues reported in the July issue of the Proceedings of the National Academy of Science (doi: 10.1073/pnas.1605635113). The improvements disappeared rapidly when the devices were turned off, but were quickly reestablished after stimulation resumed.

“This first-in-class study supports a conceptual framework for further studies of electronic medical devices in diseases currently treated with drugs, an approach termed ‘bioelectronic medicine,’” wrote Dr. Koopman of the University of Amsterdam, and her coauthors.

The team built on evidence of what they termed a “reflex neural circuit” in the vagus that strongly influences the production of inflammatory cytokines. Animal studies showed that electrical stimulation of the vagus nerve encouraged choline acetyltransferase–positive T cells to secrete acetylcholine in the spleen and other tissues. Acetylcholine binds to a class of nicotinic receptors on monocytes, macrophages, and stromal cells, and inhibits their inflammatory response.

“Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in experimental models of endotoxemia, sepsis, colitis, and other preclinical animal models of inflammatory syndromes,” the team noted.

The group reported on two human studies, totaling 25 patients. The first comprised seven patients with epilepsy who received the implanted vagus nerve stimulator for medically refractory seizures. None of these patients had a history of RA or any other inflammatory disease. The second group was all patients with active RA.

Each epilepsy patient contributed peripheral blood for study, which was collected before, during and after the implantation surgery. The team studied inflammatory markers by adding endotoxin to the samples. Those collected after the patient had been exposed to a single 30-second stimulation at 20 Hertz showed significantly inhibited production of TNF-alpha, compared with that seen in unexposed blood. Interleukin (IL)-6 and IL-1beta was also inhibited significantly by vagus nerve stimulation.

The next study involved 17 patients who had active RA, but not epilepsy. Of these, seven had failed methotrexate but were naïve to biologics; the rest had failed methotrexate and at least two biologics from different classes. Their average disease duration was 11 years.

The 86-day study gradually titrated the stimulation dose, but even at its highest, stimulation was far less than what is typically employed in epilepsy, “in which current is delivered at 60-second intervals, followed by an off interval of 5-180 minutes, repeated continuously,” the investigators wrote. “Thus, epilepsy patients may receive electrical current delivery for up to 240 minutes daily. Preclinical studies have established that stimulation of the inflammatory reflex for as little as 60 seconds confers significant inhibition of cytokine production for up to 24 hours.”

There was a 14-day post-implantation washout period with no stimulation, followed by 28 days of treatment titration. During that time, stimulation was ramped up from single 60-second stimulation with electric pulses of 250-microseconds duration at 10 Hertz and an output current between 0.25-2.0 milliamps, to the highest amperage tolerated (up to 2.0 milliamps).

That dose was the treatment target, and delivered once daily for 60 seconds in 250-microsecond pulse widths at 10 Hertz. At day 28, patients who had not had good clinical response according to EULAR response criteria, had their stimulation increased to four times daily.

In the group of seven methotrexate-resistant patients, two received electric current pulses four times daily. In the group of 10 methotrexate- and biologic-resistant patients, 6 received the four-dose stimulation.

On day 42, TNF-alpha levels in cultured peripheral blood were significantly reduced from baseline.

At that time, the vagus nerve stimulator was turned off for 14 days. By the end of the silent period, TNF-alpha levels had risen significantly from the day 42 levels. The stimulator was restarted on day 56. By day 84, after 28 more days of stimulation, TNF-alpha levels had again decreased significantly.

Symptoms and function as measured by the Disease Activity Score 28 followed a similar trajectory, improving during the initial treatment, worsening during the period of no stimulation, and improving again when stimulation was restarted. Symptom and function scores correlated positively with change in TNF levels.

The investigators also assessed the response rates according to American College of Rheumatology criteria. At day 42, 71% of those in the methotrexate-resistant group had achieved a 20% response; 57% a 50% response; and 28.6% a 70% response. Response was not as dramatic in the group resistant to both drug classes: rates were 70%, 30%, and 0%.

By day 42, nearly 30% of patients overall achieved remission, which was defined as a DAS28 score of less than 2.6. This constituted improvement in all the score components, including tender joint count, swollen joint count, patient’s assessment of pain, patient’s global assessment, physician’s global assessment, and C-reactive protein.

Finally, the investigators noted decreased levels of most serum cytokines. Most, including serum TNF, IL-10, IL-12p70, IL-13, IL-1alpha, IL-1beta, IL-2, IL-4, IL-5, and TNF-a-beta, were below 1 pg/ml.

Adverse events were common (16 patients) but reported as mild-moderate. The included hoarseness (5), hypoesthesia (4), parasthesia (2), dyspnea (2), and bradycardia (1), among others. There were no implantation-related infections. One patient reported postimplantation pain.

SetPoint Medical, of Valencia, Calif., makes the device and conducted the study. Dr. Koopman made no financial disclosures. However, several of the other authors are employees of Set Point, and of GlaxoSmithKline, which holds equity interest in the company.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

An implanted vagus nerve stimulator like that used for epilepsy treatment reduced inflammatory markers and significantly improved symptoms and function in a small cohort of patients with rheumatoid arthritis.

After 42 days, almost 30% of patients had achieved disease remission, Frieda A. Koopman, MD, and her colleagues reported in the July issue of the Proceedings of the National Academy of Science (doi: 10.1073/pnas.1605635113). The improvements disappeared rapidly when the devices were turned off, but were quickly reestablished after stimulation resumed.

“This first-in-class study supports a conceptual framework for further studies of electronic medical devices in diseases currently treated with drugs, an approach termed ‘bioelectronic medicine,’” wrote Dr. Koopman of the University of Amsterdam, and her coauthors.

The team built on evidence of what they termed a “reflex neural circuit” in the vagus that strongly influences the production of inflammatory cytokines. Animal studies showed that electrical stimulation of the vagus nerve encouraged choline acetyltransferase–positive T cells to secrete acetylcholine in the spleen and other tissues. Acetylcholine binds to a class of nicotinic receptors on monocytes, macrophages, and stromal cells, and inhibits their inflammatory response.

“Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in experimental models of endotoxemia, sepsis, colitis, and other preclinical animal models of inflammatory syndromes,” the team noted.

The group reported on two human studies, totaling 25 patients. The first comprised seven patients with epilepsy who received the implanted vagus nerve stimulator for medically refractory seizures. None of these patients had a history of RA or any other inflammatory disease. The second group was all patients with active RA.

Each epilepsy patient contributed peripheral blood for study, which was collected before, during and after the implantation surgery. The team studied inflammatory markers by adding endotoxin to the samples. Those collected after the patient had been exposed to a single 30-second stimulation at 20 Hertz showed significantly inhibited production of TNF-alpha, compared with that seen in unexposed blood. Interleukin (IL)-6 and IL-1beta was also inhibited significantly by vagus nerve stimulation.

The next study involved 17 patients who had active RA, but not epilepsy. Of these, seven had failed methotrexate but were naïve to biologics; the rest had failed methotrexate and at least two biologics from different classes. Their average disease duration was 11 years.

The 86-day study gradually titrated the stimulation dose, but even at its highest, stimulation was far less than what is typically employed in epilepsy, “in which current is delivered at 60-second intervals, followed by an off interval of 5-180 minutes, repeated continuously,” the investigators wrote. “Thus, epilepsy patients may receive electrical current delivery for up to 240 minutes daily. Preclinical studies have established that stimulation of the inflammatory reflex for as little as 60 seconds confers significant inhibition of cytokine production for up to 24 hours.”

There was a 14-day post-implantation washout period with no stimulation, followed by 28 days of treatment titration. During that time, stimulation was ramped up from single 60-second stimulation with electric pulses of 250-microseconds duration at 10 Hertz and an output current between 0.25-2.0 milliamps, to the highest amperage tolerated (up to 2.0 milliamps).

That dose was the treatment target, and delivered once daily for 60 seconds in 250-microsecond pulse widths at 10 Hertz. At day 28, patients who had not had good clinical response according to EULAR response criteria, had their stimulation increased to four times daily.

In the group of seven methotrexate-resistant patients, two received electric current pulses four times daily. In the group of 10 methotrexate- and biologic-resistant patients, 6 received the four-dose stimulation.

On day 42, TNF-alpha levels in cultured peripheral blood were significantly reduced from baseline.

At that time, the vagus nerve stimulator was turned off for 14 days. By the end of the silent period, TNF-alpha levels had risen significantly from the day 42 levels. The stimulator was restarted on day 56. By day 84, after 28 more days of stimulation, TNF-alpha levels had again decreased significantly.

Symptoms and function as measured by the Disease Activity Score 28 followed a similar trajectory, improving during the initial treatment, worsening during the period of no stimulation, and improving again when stimulation was restarted. Symptom and function scores correlated positively with change in TNF levels.

The investigators also assessed the response rates according to American College of Rheumatology criteria. At day 42, 71% of those in the methotrexate-resistant group had achieved a 20% response; 57% a 50% response; and 28.6% a 70% response. Response was not as dramatic in the group resistant to both drug classes: rates were 70%, 30%, and 0%.

By day 42, nearly 30% of patients overall achieved remission, which was defined as a DAS28 score of less than 2.6. This constituted improvement in all the score components, including tender joint count, swollen joint count, patient’s assessment of pain, patient’s global assessment, physician’s global assessment, and C-reactive protein.

Finally, the investigators noted decreased levels of most serum cytokines. Most, including serum TNF, IL-10, IL-12p70, IL-13, IL-1alpha, IL-1beta, IL-2, IL-4, IL-5, and TNF-a-beta, were below 1 pg/ml.

Adverse events were common (16 patients) but reported as mild-moderate. The included hoarseness (5), hypoesthesia (4), parasthesia (2), dyspnea (2), and bradycardia (1), among others. There were no implantation-related infections. One patient reported postimplantation pain.

SetPoint Medical, of Valencia, Calif., makes the device and conducted the study. Dr. Koopman made no financial disclosures. However, several of the other authors are employees of Set Point, and of GlaxoSmithKline, which holds equity interest in the company.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

LONDON – Biosimilar etanercept (CHS-0214) is as effective and well tolerated as etanercept (Enbrel) for the treatment of rheumatoid arthritis according to the results of a randomized, double-blind, phase III trial conducted in 13 countries.

The primary endpoint of an American College of Rheumatology (ACR) 20 at 24 weeks was achieved by 91% of patients given CHS-0214 and 90.6% of those given etanercept, giving a treatment difference of just 0.4%. The percentages of patients achieving ACR 50 (67.6% and 63.7%) and ACR 70 (38.3% and 37.9%) were also comparable.

These are the first clinical data to be presented on this biosimilar, which is a fusion protein comprising the soluble human p75 tumor necrosis factor (TNF) receptor and the Fc region of human immunoglobulin G1.

“Like all biosimilars CHD-0214 has undergone extensive analytical characterization, which had demonstrated highly similar structure and function to etanercept,” study investigator James O’Dell, MD, of the University of Nebraska Medical Center, Omaha, said at the European Congress of Rheumatology. “Studies have demonstrated that CHS-0214 is similar to etanercept with regard to in vitro pharmacology, in vivo pharmacokinetics, and toxicology,” he observed.

A total of 644 patients with moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate were enrolled in the phase III trial and randomized to receive CHS-0214 or etanercept at a subcutaneous dose of 50 mg once a week for 24 weeks. After the double-blind period had ended, patients could continue on open-label CHS-0214 for another 24 weeks. Assessment of efficacy was performed on 512 patients as an issue with the production of the biosimilar resulted in a dosing interruption for 132 patients.

Remission, defined as a DAS28-CRP (Disease Activity Score 28–C-reactive protein) score of less than 2.6, was achieved in a similar percentage of subjects in the CHS-0214 and etanercept groups, at 40.6% and 42.4%, respectively.

There was a similar percentage of any adverse event (60.8% vs. 65%) occurring among patients receiving the biosimilar and those getting etanercept. Treatment-related adverse events (16.4% vs. 21.9%), and treatment-related serious adverse events (0.9% vs. 0.3%) were also comparable. Drug-drug antibodies occurred in numerically fewer patients treated with the biosimilar than with etanercept (1.3% vs. 4.7%).

Asked after his presentation about why he thought the ACR responses seen in the study were so high, Dr. O’Dell said: “We were surprised by that.” There are a number of potential explanations, he suggested. “We had a remarkable completion rate in the trial, 95%, so we lost very few patients, and we are in the process of analyzing other trials to see if that is a major factor.” In addition, patients were on relatively lower doses of methotrexate than in some other trials “because a quarter of them came from Japan,” he said. Patients were also all biologic naive and many were recruited from countries where they don’t have the opportunity to be exposed to a lot of therapies.

“The studies on all biosimilars so far suggest that they are indeed biosimilar,” Dr. O’Dell said in an interview. So how might clinicians begin to choose between the various biosimilars? “Well, there is very, very little data to compare any biologic to another biologic,” he answered.

“You haven’t seen studies comparing one TNF inhibitor to another TNF inhibitor. So it’s not surprising that we don’t have data that compare this biosimilar to that biosimilar,” he added. Such studies are probably also unlikely to ever be conducted so the choice of biosimilar, like anti-TNF therapy is probably going to be dictated by national and local guidelines, and medical insurance policies.

“Today, the biosimilars look biosimilar, so I have no problems if somebody tells me I have to start a biosimilar as opposed to the innovator product. I do have a problem if they tell me I have to switch, because that’s interchangeability and that’s a whole different story,” he noted.

Dr. O’Dell observed, however, that data from the DANBIO registry presented during the same session had shown that an enforced national switch from infliximab (Remicade) to biosimilar infliximab had shown that this did not appear to pose a problem in routine care in Denmark. Indeed 3 months’ clinical outcomes in patients with RA, psoriatic arthritis, or axial spondyloarthritis who were switched appeared to be comparable. Whether this is true across all the biosimilars needs to be established.

Coherus Biosciences funded the study. Dr. O’Dell has been a study investigator for, received research grants from, or acted as a speaker or consultant to Coherus Biosciences, Medac, Eli Lilly, Bristol-Myers Squibb, GlaxoSmithKline, Antares, and Crescendo.

LONDON – Biosimilar etanercept (CHS-0214) is as effective and well tolerated as etanercept (Enbrel) for the treatment of rheumatoid arthritis according to the results of a randomized, double-blind, phase III trial conducted in 13 countries.

The primary endpoint of an American College of Rheumatology (ACR) 20 at 24 weeks was achieved by 91% of patients given CHS-0214 and 90.6% of those given etanercept, giving a treatment difference of just 0.4%. The percentages of patients achieving ACR 50 (67.6% and 63.7%) and ACR 70 (38.3% and 37.9%) were also comparable.

These are the first clinical data to be presented on this biosimilar, which is a fusion protein comprising the soluble human p75 tumor necrosis factor (TNF) receptor and the Fc region of human immunoglobulin G1.

“Like all biosimilars CHD-0214 has undergone extensive analytical characterization, which had demonstrated highly similar structure and function to etanercept,” study investigator James O’Dell, MD, of the University of Nebraska Medical Center, Omaha, said at the European Congress of Rheumatology. “Studies have demonstrated that CHS-0214 is similar to etanercept with regard to in vitro pharmacology, in vivo pharmacokinetics, and toxicology,” he observed.

A total of 644 patients with moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate were enrolled in the phase III trial and randomized to receive CHS-0214 or etanercept at a subcutaneous dose of 50 mg once a week for 24 weeks. After the double-blind period had ended, patients could continue on open-label CHS-0214 for another 24 weeks. Assessment of efficacy was performed on 512 patients as an issue with the production of the biosimilar resulted in a dosing interruption for 132 patients.

Remission, defined as a DAS28-CRP (Disease Activity Score 28–C-reactive protein) score of less than 2.6, was achieved in a similar percentage of subjects in the CHS-0214 and etanercept groups, at 40.6% and 42.4%, respectively.

There was a similar percentage of any adverse event (60.8% vs. 65%) occurring among patients receiving the biosimilar and those getting etanercept. Treatment-related adverse events (16.4% vs. 21.9%), and treatment-related serious adverse events (0.9% vs. 0.3%) were also comparable. Drug-drug antibodies occurred in numerically fewer patients treated with the biosimilar than with etanercept (1.3% vs. 4.7%).

Asked after his presentation about why he thought the ACR responses seen in the study were so high, Dr. O’Dell said: “We were surprised by that.” There are a number of potential explanations, he suggested. “We had a remarkable completion rate in the trial, 95%, so we lost very few patients, and we are in the process of analyzing other trials to see if that is a major factor.” In addition, patients were on relatively lower doses of methotrexate than in some other trials “because a quarter of them came from Japan,” he said. Patients were also all biologic naive and many were recruited from countries where they don’t have the opportunity to be exposed to a lot of therapies.

“The studies on all biosimilars so far suggest that they are indeed biosimilar,” Dr. O’Dell said in an interview. So how might clinicians begin to choose between the various biosimilars? “Well, there is very, very little data to compare any biologic to another biologic,” he answered.

“You haven’t seen studies comparing one TNF inhibitor to another TNF inhibitor. So it’s not surprising that we don’t have data that compare this biosimilar to that biosimilar,” he added. Such studies are probably also unlikely to ever be conducted so the choice of biosimilar, like anti-TNF therapy is probably going to be dictated by national and local guidelines, and medical insurance policies.

“Today, the biosimilars look biosimilar, so I have no problems if somebody tells me I have to start a biosimilar as opposed to the innovator product. I do have a problem if they tell me I have to switch, because that’s interchangeability and that’s a whole different story,” he noted.

Dr. O’Dell observed, however, that data from the DANBIO registry presented during the same session had shown that an enforced national switch from infliximab (Remicade) to biosimilar infliximab had shown that this did not appear to pose a problem in routine care in Denmark. Indeed 3 months’ clinical outcomes in patients with RA, psoriatic arthritis, or axial spondyloarthritis who were switched appeared to be comparable. Whether this is true across all the biosimilars needs to be established.

Coherus Biosciences funded the study. Dr. O’Dell has been a study investigator for, received research grants from, or acted as a speaker or consultant to Coherus Biosciences, Medac, Eli Lilly, Bristol-Myers Squibb, GlaxoSmithKline, Antares, and Crescendo.

LONDON – Biosimilar etanercept (CHS-0214) is as effective and well tolerated as etanercept (Enbrel) for the treatment of rheumatoid arthritis according to the results of a randomized, double-blind, phase III trial conducted in 13 countries.

The primary endpoint of an American College of Rheumatology (ACR) 20 at 24 weeks was achieved by 91% of patients given CHS-0214 and 90.6% of those given etanercept, giving a treatment difference of just 0.4%. The percentages of patients achieving ACR 50 (67.6% and 63.7%) and ACR 70 (38.3% and 37.9%) were also comparable.

These are the first clinical data to be presented on this biosimilar, which is a fusion protein comprising the soluble human p75 tumor necrosis factor (TNF) receptor and the Fc region of human immunoglobulin G1.

“Like all biosimilars CHD-0214 has undergone extensive analytical characterization, which had demonstrated highly similar structure and function to etanercept,” study investigator James O’Dell, MD, of the University of Nebraska Medical Center, Omaha, said at the European Congress of Rheumatology. “Studies have demonstrated that CHS-0214 is similar to etanercept with regard to in vitro pharmacology, in vivo pharmacokinetics, and toxicology,” he observed.

A total of 644 patients with moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate were enrolled in the phase III trial and randomized to receive CHS-0214 or etanercept at a subcutaneous dose of 50 mg once a week for 24 weeks. After the double-blind period had ended, patients could continue on open-label CHS-0214 for another 24 weeks. Assessment of efficacy was performed on 512 patients as an issue with the production of the biosimilar resulted in a dosing interruption for 132 patients.

Remission, defined as a DAS28-CRP (Disease Activity Score 28–C-reactive protein) score of less than 2.6, was achieved in a similar percentage of subjects in the CHS-0214 and etanercept groups, at 40.6% and 42.4%, respectively.

There was a similar percentage of any adverse event (60.8% vs. 65%) occurring among patients receiving the biosimilar and those getting etanercept. Treatment-related adverse events (16.4% vs. 21.9%), and treatment-related serious adverse events (0.9% vs. 0.3%) were also comparable. Drug-drug antibodies occurred in numerically fewer patients treated with the biosimilar than with etanercept (1.3% vs. 4.7%).

Asked after his presentation about why he thought the ACR responses seen in the study were so high, Dr. O’Dell said: “We were surprised by that.” There are a number of potential explanations, he suggested. “We had a remarkable completion rate in the trial, 95%, so we lost very few patients, and we are in the process of analyzing other trials to see if that is a major factor.” In addition, patients were on relatively lower doses of methotrexate than in some other trials “because a quarter of them came from Japan,” he said. Patients were also all biologic naive and many were recruited from countries where they don’t have the opportunity to be exposed to a lot of therapies.

“The studies on all biosimilars so far suggest that they are indeed biosimilar,” Dr. O’Dell said in an interview. So how might clinicians begin to choose between the various biosimilars? “Well, there is very, very little data to compare any biologic to another biologic,” he answered.

“You haven’t seen studies comparing one TNF inhibitor to another TNF inhibitor. So it’s not surprising that we don’t have data that compare this biosimilar to that biosimilar,” he added. Such studies are probably also unlikely to ever be conducted so the choice of biosimilar, like anti-TNF therapy is probably going to be dictated by national and local guidelines, and medical insurance policies.

“Today, the biosimilars look biosimilar, so I have no problems if somebody tells me I have to start a biosimilar as opposed to the innovator product. I do have a problem if they tell me I have to switch, because that’s interchangeability and that’s a whole different story,” he noted.

Dr. O’Dell observed, however, that data from the DANBIO registry presented during the same session had shown that an enforced national switch from infliximab (Remicade) to biosimilar infliximab had shown that this did not appear to pose a problem in routine care in Denmark. Indeed 3 months’ clinical outcomes in patients with RA, psoriatic arthritis, or axial spondyloarthritis who were switched appeared to be comparable. Whether this is true across all the biosimilars needs to be established.

Coherus Biosciences funded the study. Dr. O’Dell has been a study investigator for, received research grants from, or acted as a speaker or consultant to Coherus Biosciences, Medac, Eli Lilly, Bristol-Myers Squibb, GlaxoSmithKline, Antares, and Crescendo.

LONDON – ABT-494 and filgotinib – two investigational and highly selective oral Janus kinase-1 inhibitors – are both showing promise in the treatment of patients with rheumatoid arthritis, according to the results of two separate phase II studies presented at the European Congress of Rheumatology.

In the BALANCE-2 study, 62%-80% patients who had an inadequate response to methotrexate alone achieved the primary endpoint of an ACR20 response after 12 weeks of combination treatment with methotrexate and ABT-494, depending on the dose used, versus 46% for placebo plus methotrexate. The secondary endpoint of ACR50 was reached by a respective 38%-50% vs. 18%, and ACR70 response was achieved by 16%-28% vs. 6%.

And in the DARWIN-1 study, 56%-79% of patients treated with different doses of filgotinib plus methotrexate achieved the trial’s primary endpoint, which was again ACR20 at 12 weeks, versus 44% for placebo plus methotrexate. ACR50 and ACR70 responses were also similarly high and maintained up to 24 weeks of follow-up.

Both drugs had safety and tolerability data that supported their further development, the respective study investigators said.

“I think the results are rather straightforward. There was significant improvement in signs and symptoms of RA with fast onset,” said René Westhovens, MD, PhD, of the University of Leuven (Belgium), who presented the data from the DARWIN-1 study. “These robust data support the future development of filgotinib in RA,” he said.

Mark Genovese, MD, of Stanford (Calif.) University, who presented the findings of the BALANCE-2 study, said: “ABT-494 has been shown to have significant improvements in symptoms and signs [of RA] based on our endpoints of ACR [response], DAS[28], and CDAI [clinical disease activity index].” Like ACR50 and ACR70, DAS28 and CDAI were secondary efficacy endpoints and showed significantly greater changes from baseline versus placebo, started from around 2 weeks.

In an interview, Peter Taylor, PhD, who chaired the session at the meeting where the findings were presented, said: “We’ve seen a lot of data about JAK inhibitors at various stages of development at EULAR 2016, with varying selectivity, and the clinical data unequivocally validates Janus kinases as a therapeutic target.”

Dr. Taylor, the Norman Collisson Professor of Musculoskeletal Sciences at the University of Oxford (England), added: “[JAK inhibitors] show very significant promise with favorable safety data overall, but there are subtle differences between the drugs which need further detailed analysis to understand what it means in a clinical context.”

BALANCE-2 was a double-blind, placebo-controlled, dose-ranging phase IIB study designed to look at the safety and efficacy of ABT-494 in adult patients with moderately to severely active rheumatoid arthritis who had an inadequate response to methotrexate. Five doses of ABT-494 were tested: four given twice-daily (3, 6, 12, and 18 mg) and one given once-daily (24 mg). A total of 300 patients were enrolled and 299 were randomized, 50 to placebo, 50 each to the once-daily doses, and 49 to the twice-daily dose group. The mean weekly methotrexate dose at baseline was 14-16 mg across the groups.

“In general, the safety and tolerability of ABT-494 was satisfactory at the doses tested, consistent with what would have been expected,” Dr. Genovese said.

There was a numerically higher rate of any adverse event in the groups treated with ABT-494, at 40%, 46%, 58%, and 50% for the twice-daily regimens of 3, 6, 12, and 18 mg, as well as 35% for the once-daily 24-mg dose. The rate was 26% for placebo plus methotrexate.

Infections occurred in a respective 20%, 14%, 24%, 22% across the twice-daily dosing groups, respectively, compared with 18% for the once-daily 24-mg dose and 14% for placebo plus methotrexate, he noted. While there were some grade 2-3 abnormalities in liver enzymes and dose-related decreases in hemoglobin seen at higher doses, these did not appear to have significant clinical impact. The ratio of high-density lipoprotein cholesterol (HDL-C) to low-density lipoprotein cholesterol (LDL-C) was also affected slightly.

DARWIN-1 involved a total of 599 enrolled and 594 randomized and exposed patients with RA treated with placebo plus methotrexate or methotrexate plus one of six dosing regimens of filgotinib: 50, 100, or 200 mg once daily, or 25, 50, or 100 mg twice daily, for 24 weeks, with around 85 patients in each group. Each patient previously had an inadequate response to methotrexate alone. At the 12-week halfway point, patients taking placebo and the 50-mg dose could be reassigned to filgotinib 100 mg once daily or 50 mg twice daily if their tender or swollen joint counts had not improved. The mean weekly dose of methotrexate at baseline was 16.4-17.5 mg across the groups.

In addition to the improved ACR responses, significant improvements with filgotinib versus placebo were seen in the secondary endpoints of DAS28 (including DAS28 based on C-reactive protein), CDAI, and the Health Assessment Questionnaire-Disability Index.

There were infrequent serious adverse events, which included serious infections, and adverse events leading to discontinuations, Dr. Westhovens observed, and nothing that would not have been expected or different from placebo. There was a small decrease in neutrophil counts and increase in creatinine, but neither had any clinical consequences. Interestingly, there was a dose-dependent increase in hemoglobin but no reduction in lymphocyte counts, he said. HDL-C increased more than LDL-C.

Five phase III trials with ABT-494 are currently underway in patients with RA:

• SELECT-COMPARE will enroll an estimated 1,500 RA patients who have had an inadequate response to a stable dose of methotrexate and will compare additional treatment with ABT-494 against additional treatment with adalimumab (Humira) or placebo.

• SELECT-NEXT will enroll an estimated 600 RA patients who have had an inadequate response to stable doses of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and are then given ABT-494 or placebo on top.

• SELECT-BEYOND will enroll around 450 RA patients on stable csDMARDs who have an inadequate response or intolerance to biologic DMARDs and compare adding ABT-494 or placebo.

• SELECT-MONOTHERAPY will enroll 600 RA patients who have had an inadequate methotrexate response and compare ABT-494 monotherapy to methotrexate monotherapy.

• SELECT-EARLY will enroll 975 methotrexate-naive, moderately-to-severely active RA patients and compare giving ABT-494 monotherapy to methotrexate monotherapy.

Most of these trials should have primary endpoint data available for analysis by mid to late 2017 or 2018 and be finished by 2020 or 2021.

Filgotinib, formerly known as GLPG0634, is also about to enter phase III trials, but the details of these trials have not yet been revealed other than that they will begin mid-2016.

The BALANCE-2 study was funded by AbbVie. Dr. Genovese is a consultant for, and has received grants from AbbVie, Eli Lilly, Astellas, Vertex, Pfizer, Galapagos, and Gilead.

The DARWIN-1 study was funded by Galapagos. Dr. Westhovens is the principal investigator for the study. He also disclosed receiving research funding from Roche and speaker’s honoraria from Bristol-Myers Squibb.

Dr. Taylor was not involved in either study but has consulted for Eli Lilly, Pfizer, and Galapagos.

LONDON – ABT-494 and filgotinib – two investigational and highly selective oral Janus kinase-1 inhibitors – are both showing promise in the treatment of patients with rheumatoid arthritis, according to the results of two separate phase II studies presented at the European Congress of Rheumatology.

In the BALANCE-2 study, 62%-80% patients who had an inadequate response to methotrexate alone achieved the primary endpoint of an ACR20 response after 12 weeks of combination treatment with methotrexate and ABT-494, depending on the dose used, versus 46% for placebo plus methotrexate. The secondary endpoint of ACR50 was reached by a respective 38%-50% vs. 18%, and ACR70 response was achieved by 16%-28% vs. 6%.

And in the DARWIN-1 study, 56%-79% of patients treated with different doses of filgotinib plus methotrexate achieved the trial’s primary endpoint, which was again ACR20 at 12 weeks, versus 44% for placebo plus methotrexate. ACR50 and ACR70 responses were also similarly high and maintained up to 24 weeks of follow-up.

Both drugs had safety and tolerability data that supported their further development, the respective study investigators said.

“I think the results are rather straightforward. There was significant improvement in signs and symptoms of RA with fast onset,” said René Westhovens, MD, PhD, of the University of Leuven (Belgium), who presented the data from the DARWIN-1 study. “These robust data support the future development of filgotinib in RA,” he said.

Mark Genovese, MD, of Stanford (Calif.) University, who presented the findings of the BALANCE-2 study, said: “ABT-494 has been shown to have significant improvements in symptoms and signs [of RA] based on our endpoints of ACR [response], DAS[28], and CDAI [clinical disease activity index].” Like ACR50 and ACR70, DAS28 and CDAI were secondary efficacy endpoints and showed significantly greater changes from baseline versus placebo, started from around 2 weeks.

In an interview, Peter Taylor, PhD, who chaired the session at the meeting where the findings were presented, said: “We’ve seen a lot of data about JAK inhibitors at various stages of development at EULAR 2016, with varying selectivity, and the clinical data unequivocally validates Janus kinases as a therapeutic target.”

Dr. Taylor, the Norman Collisson Professor of Musculoskeletal Sciences at the University of Oxford (England), added: “[JAK inhibitors] show very significant promise with favorable safety data overall, but there are subtle differences between the drugs which need further detailed analysis to understand what it means in a clinical context.”

BALANCE-2 was a double-blind, placebo-controlled, dose-ranging phase IIB study designed to look at the safety and efficacy of ABT-494 in adult patients with moderately to severely active rheumatoid arthritis who had an inadequate response to methotrexate. Five doses of ABT-494 were tested: four given twice-daily (3, 6, 12, and 18 mg) and one given once-daily (24 mg). A total of 300 patients were enrolled and 299 were randomized, 50 to placebo, 50 each to the once-daily doses, and 49 to the twice-daily dose group. The mean weekly methotrexate dose at baseline was 14-16 mg across the groups.

“In general, the safety and tolerability of ABT-494 was satisfactory at the doses tested, consistent with what would have been expected,” Dr. Genovese said.

There was a numerically higher rate of any adverse event in the groups treated with ABT-494, at 40%, 46%, 58%, and 50% for the twice-daily regimens of 3, 6, 12, and 18 mg, as well as 35% for the once-daily 24-mg dose. The rate was 26% for placebo plus methotrexate.

Infections occurred in a respective 20%, 14%, 24%, 22% across the twice-daily dosing groups, respectively, compared with 18% for the once-daily 24-mg dose and 14% for placebo plus methotrexate, he noted. While there were some grade 2-3 abnormalities in liver enzymes and dose-related decreases in hemoglobin seen at higher doses, these did not appear to have significant clinical impact. The ratio of high-density lipoprotein cholesterol (HDL-C) to low-density lipoprotein cholesterol (LDL-C) was also affected slightly.

DARWIN-1 involved a total of 599 enrolled and 594 randomized and exposed patients with RA treated with placebo plus methotrexate or methotrexate plus one of six dosing regimens of filgotinib: 50, 100, or 200 mg once daily, or 25, 50, or 100 mg twice daily, for 24 weeks, with around 85 patients in each group. Each patient previously had an inadequate response to methotrexate alone. At the 12-week halfway point, patients taking placebo and the 50-mg dose could be reassigned to filgotinib 100 mg once daily or 50 mg twice daily if their tender or swollen joint counts had not improved. The mean weekly dose of methotrexate at baseline was 16.4-17.5 mg across the groups.

In addition to the improved ACR responses, significant improvements with filgotinib versus placebo were seen in the secondary endpoints of DAS28 (including DAS28 based on C-reactive protein), CDAI, and the Health Assessment Questionnaire-Disability Index.

There were infrequent serious adverse events, which included serious infections, and adverse events leading to discontinuations, Dr. Westhovens observed, and nothing that would not have been expected or different from placebo. There was a small decrease in neutrophil counts and increase in creatinine, but neither had any clinical consequences. Interestingly, there was a dose-dependent increase in hemoglobin but no reduction in lymphocyte counts, he said. HDL-C increased more than LDL-C.

Five phase III trials with ABT-494 are currently underway in patients with RA:

• SELECT-COMPARE will enroll an estimated 1,500 RA patients who have had an inadequate response to a stable dose of methotrexate and will compare additional treatment with ABT-494 against additional treatment with adalimumab (Humira) or placebo.

• SELECT-NEXT will enroll an estimated 600 RA patients who have had an inadequate response to stable doses of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and are then given ABT-494 or placebo on top.

• SELECT-BEYOND will enroll around 450 RA patients on stable csDMARDs who have an inadequate response or intolerance to biologic DMARDs and compare adding ABT-494 or placebo.

• SELECT-MONOTHERAPY will enroll 600 RA patients who have had an inadequate methotrexate response and compare ABT-494 monotherapy to methotrexate monotherapy.

• SELECT-EARLY will enroll 975 methotrexate-naive, moderately-to-severely active RA patients and compare giving ABT-494 monotherapy to methotrexate monotherapy.

Most of these trials should have primary endpoint data available for analysis by mid to late 2017 or 2018 and be finished by 2020 or 2021.

Filgotinib, formerly known as GLPG0634, is also about to enter phase III trials, but the details of these trials have not yet been revealed other than that they will begin mid-2016.

The BALANCE-2 study was funded by AbbVie. Dr. Genovese is a consultant for, and has received grants from AbbVie, Eli Lilly, Astellas, Vertex, Pfizer, Galapagos, and Gilead.

The DARWIN-1 study was funded by Galapagos. Dr. Westhovens is the principal investigator for the study. He also disclosed receiving research funding from Roche and speaker’s honoraria from Bristol-Myers Squibb.

Dr. Taylor was not involved in either study but has consulted for Eli Lilly, Pfizer, and Galapagos.

LONDON – ABT-494 and filgotinib – two investigational and highly selective oral Janus kinase-1 inhibitors – are both showing promise in the treatment of patients with rheumatoid arthritis, according to the results of two separate phase II studies presented at the European Congress of Rheumatology.

In the BALANCE-2 study, 62%-80% patients who had an inadequate response to methotrexate alone achieved the primary endpoint of an ACR20 response after 12 weeks of combination treatment with methotrexate and ABT-494, depending on the dose used, versus 46% for placebo plus methotrexate. The secondary endpoint of ACR50 was reached by a respective 38%-50% vs. 18%, and ACR70 response was achieved by 16%-28% vs. 6%.

And in the DARWIN-1 study, 56%-79% of patients treated with different doses of filgotinib plus methotrexate achieved the trial’s primary endpoint, which was again ACR20 at 12 weeks, versus 44% for placebo plus methotrexate. ACR50 and ACR70 responses were also similarly high and maintained up to 24 weeks of follow-up.

Both drugs had safety and tolerability data that supported their further development, the respective study investigators said.

“I think the results are rather straightforward. There was significant improvement in signs and symptoms of RA with fast onset,” said René Westhovens, MD, PhD, of the University of Leuven (Belgium), who presented the data from the DARWIN-1 study. “These robust data support the future development of filgotinib in RA,” he said.

Mark Genovese, MD, of Stanford (Calif.) University, who presented the findings of the BALANCE-2 study, said: “ABT-494 has been shown to have significant improvements in symptoms and signs [of RA] based on our endpoints of ACR [response], DAS[28], and CDAI [clinical disease activity index].” Like ACR50 and ACR70, DAS28 and CDAI were secondary efficacy endpoints and showed significantly greater changes from baseline versus placebo, started from around 2 weeks.

In an interview, Peter Taylor, PhD, who chaired the session at the meeting where the findings were presented, said: “We’ve seen a lot of data about JAK inhibitors at various stages of development at EULAR 2016, with varying selectivity, and the clinical data unequivocally validates Janus kinases as a therapeutic target.”

Dr. Taylor, the Norman Collisson Professor of Musculoskeletal Sciences at the University of Oxford (England), added: “[JAK inhibitors] show very significant promise with favorable safety data overall, but there are subtle differences between the drugs which need further detailed analysis to understand what it means in a clinical context.”

BALANCE-2 was a double-blind, placebo-controlled, dose-ranging phase IIB study designed to look at the safety and efficacy of ABT-494 in adult patients with moderately to severely active rheumatoid arthritis who had an inadequate response to methotrexate. Five doses of ABT-494 were tested: four given twice-daily (3, 6, 12, and 18 mg) and one given once-daily (24 mg). A total of 300 patients were enrolled and 299 were randomized, 50 to placebo, 50 each to the once-daily doses, and 49 to the twice-daily dose group. The mean weekly methotrexate dose at baseline was 14-16 mg across the groups.

“In general, the safety and tolerability of ABT-494 was satisfactory at the doses tested, consistent with what would have been expected,” Dr. Genovese said.

There was a numerically higher rate of any adverse event in the groups treated with ABT-494, at 40%, 46%, 58%, and 50% for the twice-daily regimens of 3, 6, 12, and 18 mg, as well as 35% for the once-daily 24-mg dose. The rate was 26% for placebo plus methotrexate.

Infections occurred in a respective 20%, 14%, 24%, 22% across the twice-daily dosing groups, respectively, compared with 18% for the once-daily 24-mg dose and 14% for placebo plus methotrexate, he noted. While there were some grade 2-3 abnormalities in liver enzymes and dose-related decreases in hemoglobin seen at higher doses, these did not appear to have significant clinical impact. The ratio of high-density lipoprotein cholesterol (HDL-C) to low-density lipoprotein cholesterol (LDL-C) was also affected slightly.

DARWIN-1 involved a total of 599 enrolled and 594 randomized and exposed patients with RA treated with placebo plus methotrexate or methotrexate plus one of six dosing regimens of filgotinib: 50, 100, or 200 mg once daily, or 25, 50, or 100 mg twice daily, for 24 weeks, with around 85 patients in each group. Each patient previously had an inadequate response to methotrexate alone. At the 12-week halfway point, patients taking placebo and the 50-mg dose could be reassigned to filgotinib 100 mg once daily or 50 mg twice daily if their tender or swollen joint counts had not improved. The mean weekly dose of methotrexate at baseline was 16.4-17.5 mg across the groups.

In addition to the improved ACR responses, significant improvements with filgotinib versus placebo were seen in the secondary endpoints of DAS28 (including DAS28 based on C-reactive protein), CDAI, and the Health Assessment Questionnaire-Disability Index.

There were infrequent serious adverse events, which included serious infections, and adverse events leading to discontinuations, Dr. Westhovens observed, and nothing that would not have been expected or different from placebo. There was a small decrease in neutrophil counts and increase in creatinine, but neither had any clinical consequences. Interestingly, there was a dose-dependent increase in hemoglobin but no reduction in lymphocyte counts, he said. HDL-C increased more than LDL-C.

Five phase III trials with ABT-494 are currently underway in patients with RA:

• SELECT-COMPARE will enroll an estimated 1,500 RA patients who have had an inadequate response to a stable dose of methotrexate and will compare additional treatment with ABT-494 against additional treatment with adalimumab (Humira) or placebo.

• SELECT-NEXT will enroll an estimated 600 RA patients who have had an inadequate response to stable doses of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and are then given ABT-494 or placebo on top.

• SELECT-BEYOND will enroll around 450 RA patients on stable csDMARDs who have an inadequate response or intolerance to biologic DMARDs and compare adding ABT-494 or placebo.

• SELECT-MONOTHERAPY will enroll 600 RA patients who have had an inadequate methotrexate response and compare ABT-494 monotherapy to methotrexate monotherapy.

• SELECT-EARLY will enroll 975 methotrexate-naive, moderately-to-severely active RA patients and compare giving ABT-494 monotherapy to methotrexate monotherapy.

Most of these trials should have primary endpoint data available for analysis by mid to late 2017 or 2018 and be finished by 2020 or 2021.

Filgotinib, formerly known as GLPG0634, is also about to enter phase III trials, but the details of these trials have not yet been revealed other than that they will begin mid-2016.

The BALANCE-2 study was funded by AbbVie. Dr. Genovese is a consultant for, and has received grants from AbbVie, Eli Lilly, Astellas, Vertex, Pfizer, Galapagos, and Gilead.

The DARWIN-1 study was funded by Galapagos. Dr. Westhovens is the principal investigator for the study. He also disclosed receiving research funding from Roche and speaker’s honoraria from Bristol-Myers Squibb.

Dr. Taylor was not involved in either study but has consulted for Eli Lilly, Pfizer, and Galapagos.

The U.S. Food and Drug Administration has approved adalimumab for treatment of noninfectious intermediate, posterior, and panuveitis in adults, making it the only approved drug for the condition that is not a corticosteroid.

The approval marks the 10th approved indication for adalimumab (Humira) in the United States. It was recently approved for this indication in the European Union as well.

Patients on adalimumab had about half the risk of those on placebo to experience treatment failure (a combination of uveitis flare and decrease in visual acuity) in two pivotal phase III studies, VISUAL-I (hazard ratio, 0.5 for VISUAL-I; P less than .001) and VISUAL-II (HR, 0.57; P = .004). In the trials, patients were treated with an 80-mg loading dose of adalimumab at baseline, followed by a 40-mg subcutaneous injection at week 1 and then 40 mg every other week for up to 80 weeks.

“These approvals provide a valuable option for patients experiencing flare and vision impairment associated with this group of inflammatory diseases of the eye,” Glenn J. Jaffe, MD, of Duke University, Durham, N.C., said in an announcement from the manufacturer of adalimumab, AbbVie. “Data from the robust VISUAL clinical trial program demonstrate the value of Humira as a treatment option for patients with these serious diseases.”

llaubach@frontlinemedcom.com

The U.S. Food and Drug Administration has approved adalimumab for treatment of noninfectious intermediate, posterior, and panuveitis in adults, making it the only approved drug for the condition that is not a corticosteroid.

The approval marks the 10th approved indication for adalimumab (Humira) in the United States. It was recently approved for this indication in the European Union as well.

Patients on adalimumab had about half the risk of those on placebo to experience treatment failure (a combination of uveitis flare and decrease in visual acuity) in two pivotal phase III studies, VISUAL-I (hazard ratio, 0.5 for VISUAL-I; P less than .001) and VISUAL-II (HR, 0.57; P = .004). In the trials, patients were treated with an 80-mg loading dose of adalimumab at baseline, followed by a 40-mg subcutaneous injection at week 1 and then 40 mg every other week for up to 80 weeks.

“These approvals provide a valuable option for patients experiencing flare and vision impairment associated with this group of inflammatory diseases of the eye,” Glenn J. Jaffe, MD, of Duke University, Durham, N.C., said in an announcement from the manufacturer of adalimumab, AbbVie. “Data from the robust VISUAL clinical trial program demonstrate the value of Humira as a treatment option for patients with these serious diseases.”

llaubach@frontlinemedcom.com

The U.S. Food and Drug Administration has approved adalimumab for treatment of noninfectious intermediate, posterior, and panuveitis in adults, making it the only approved drug for the condition that is not a corticosteroid.

The approval marks the 10th approved indication for adalimumab (Humira) in the United States. It was recently approved for this indication in the European Union as well.

Patients on adalimumab had about half the risk of those on placebo to experience treatment failure (a combination of uveitis flare and decrease in visual acuity) in two pivotal phase III studies, VISUAL-I (hazard ratio, 0.5 for VISUAL-I; P less than .001) and VISUAL-II (HR, 0.57; P = .004). In the trials, patients were treated with an 80-mg loading dose of adalimumab at baseline, followed by a 40-mg subcutaneous injection at week 1 and then 40 mg every other week for up to 80 weeks.

“These approvals provide a valuable option for patients experiencing flare and vision impairment associated with this group of inflammatory diseases of the eye,” Glenn J. Jaffe, MD, of Duke University, Durham, N.C., said in an announcement from the manufacturer of adalimumab, AbbVie. “Data from the robust VISUAL clinical trial program demonstrate the value of Humira as a treatment option for patients with these serious diseases.”

llaubach@frontlinemedcom.com

LONDON – Retinopathy in patients taking long-term hydroxychloroquine for rheumatic conditions requires assessment by those experienced with specialized ophthalmic imaging, according to study findings presented at the European Congress of Rheumatology.

Nonspecific abnormalities, which often are unrelated to hydroxychloroquine (HCQ), can be seen with many of the tests recommended by current ophthalmology guidelines. These changes need “careful interpretation by retina specialists,” the study’s investigators wrote in a poster presentation.

HCQ is used widely for the treatment of systemic lupus erythematosus (SLE), rheumatoid arthritis, and many other inflammatory or autoimmune conditions, but it can cause irreversible eye damage and is often associated with prolonged (greater than 5 years) use. Specifically, it can cause a type of end-stage retinopathy called bull’s-eye maculopathy, which is where the fovea becomes hyperpigmented, much like the bull’s-eye on a dartboard. This can lead to substantial vision loss (blind spots) if not caught early.

Although it is reasonably rare to develop end-stage retinopathy, there is currently no treatment for HCQ-induced retinopathy. Stopping the drug may not necessarily stop the retinal damage, and drug withdrawal may not be an option in many patients given the lack of alternative options to treat the symptoms of SLE, study author and ophthalmologist Syed Mahmood Ali Shah, MBBS, MD, said in an interview.

Dr. Shah and his associates at Johns Hopkins University in Baltimore reported on applying the 2011 American Academy of Ophthalmology (AAO) guidelines on screening for HCQ retinopathy (Ophthalmology. 2011;118:415-22) to an academic practice. They also estimated the prevalence of HCQ retinopathy among 135 consecutively treated patients with SLE using recommended tests. The mean duration of HCQ use was 12.5 years.

The 2011 AAO guidelines – which in March 2016 were updated (Ophthalmology 2016 Jun;123:1386-94) – recommended the use of three “ancillary” tests in addition to the usual clinical ophthalmic examination and assessment of visual fields: optical coherence tomography (OCT), fundus autofluorescence (FAF), and multifocal electroretinography (mfERG). Dr. Shah and his colleagues used these three tests together with eye-tracking microperimetry (MP) as a substitute for Humphrey Visual Fields (HVF), which is a common visual field test used in the United States.

Courtesy Syed Mahmood Ali Shah, MBBS, MD

One difference between the 2011 guidelines and 2016 revision is that “the baseline exam can now be performed relying [only] on the fundus exam, with additional imaging required only for abnormal patients,” Dr. Shah said. “Overall, the guidelines have not changed on how often and how much you follow up,” he added. “The change is that there is no need to do these tests at baseline unless changes of the fundus are present.” However, OCT has become more widely used in many offices and has been recognized as the most useful objective test and shall be performed if there are any abnormal findings of the fundus.

A total of 266 eyes were examined using these imaging methods and interpreted by experienced retina specialists. Overall, HCQ-related abnormalities were noted in 14 (5%) eyes using OCT, 18 (7%) using FAF, 27 (10%) eyes using mfERG, and 20 (7%) using MP.

MP had the lowest discrepancy between the overall number of eyes with abnormalities (72 [27%] of 266) detected and the number of eyes with abnormalities related to HCQ (20 [28%] of 72), followed by OCT (21% and 25%, respectively), FAF (19% and 35%) and mfERG (37% and 28%). Only four patients (3%) showed changes in all four tests suggestive of HCQ retinopathy.

Courtesy Syed Mahmood Ali Shah, MBBS, MD

In the absence of baseline data from the AAO recommended ancillary tests before the use of HCQ, “it may be difficult to interpret changes seen on these tests since most of the screenings are done by regular ophthalmologists who lack the equipment and experience with specialized testing such as mfERG, FAF, and OCT,” Dr. Shah and his coauthors noted. “We found a substantial number of cases with abnormalities unrelated to HCQ.”

Giving some practical advice, Dr. Shah noted that “before a patient starts treatment with HCQ, they should undergo a baseline ophthalmic assessment. Then if the patient complains of any vision changes, even if they have been taking the drug for less than 5 years, they should be reassessed.”

While repeat follow-up is, of course, necessary, he intimated that it is necessary to find a balance of risk and cost in regard to the frequency of screening for drug-related damage. “The American Academy of Ophthalmology currently recommends that a baseline fundus exam be performed shortly after starting HCQ. Ancillary OCT and visual fields shall only be performed if the fundus is abnormal at this baseline exam. However, since most retina specialists get OCT and visual field testing anyway it is wise to look at these as well,” he suggested. After 5 years of using the drug, they must be seen more regularly, and this is the point when ophthalmologists can decide if this should be every 6 months or annually, with the latter recommended by the AAO guidelines for patients with no additional risk factors.

The study was supported by noncommercial grants. Dr. Shah had no conflicts of interest to disclose.

LONDON – Retinopathy in patients taking long-term hydroxychloroquine for rheumatic conditions requires assessment by those experienced with specialized ophthalmic imaging, according to study findings presented at the European Congress of Rheumatology.

Nonspecific abnormalities, which often are unrelated to hydroxychloroquine (HCQ), can be seen with many of the tests recommended by current ophthalmology guidelines. These changes need “careful interpretation by retina specialists,” the study’s investigators wrote in a poster presentation.

HCQ is used widely for the treatment of systemic lupus erythematosus (SLE), rheumatoid arthritis, and many other inflammatory or autoimmune conditions, but it can cause irreversible eye damage and is often associated with prolonged (greater than 5 years) use. Specifically, it can cause a type of end-stage retinopathy called bull’s-eye maculopathy, which is where the fovea becomes hyperpigmented, much like the bull’s-eye on a dartboard. This can lead to substantial vision loss (blind spots) if not caught early.

Although it is reasonably rare to develop end-stage retinopathy, there is currently no treatment for HCQ-induced retinopathy. Stopping the drug may not necessarily stop the retinal damage, and drug withdrawal may not be an option in many patients given the lack of alternative options to treat the symptoms of SLE, study author and ophthalmologist Syed Mahmood Ali Shah, MBBS, MD, said in an interview.

Dr. Shah and his associates at Johns Hopkins University in Baltimore reported on applying the 2011 American Academy of Ophthalmology (AAO) guidelines on screening for HCQ retinopathy (Ophthalmology. 2011;118:415-22) to an academic practice. They also estimated the prevalence of HCQ retinopathy among 135 consecutively treated patients with SLE using recommended tests. The mean duration of HCQ use was 12.5 years.

The 2011 AAO guidelines – which in March 2016 were updated (Ophthalmology 2016 Jun;123:1386-94) – recommended the use of three “ancillary” tests in addition to the usual clinical ophthalmic examination and assessment of visual fields: optical coherence tomography (OCT), fundus autofluorescence (FAF), and multifocal electroretinography (mfERG). Dr. Shah and his colleagues used these three tests together with eye-tracking microperimetry (MP) as a substitute for Humphrey Visual Fields (HVF), which is a common visual field test used in the United States.

Courtesy Syed Mahmood Ali Shah, MBBS, MD

One difference between the 2011 guidelines and 2016 revision is that “the baseline exam can now be performed relying [only] on the fundus exam, with additional imaging required only for abnormal patients,” Dr. Shah said. “Overall, the guidelines have not changed on how often and how much you follow up,” he added. “The change is that there is no need to do these tests at baseline unless changes of the fundus are present.” However, OCT has become more widely used in many offices and has been recognized as the most useful objective test and shall be performed if there are any abnormal findings of the fundus.

A total of 266 eyes were examined using these imaging methods and interpreted by experienced retina specialists. Overall, HCQ-related abnormalities were noted in 14 (5%) eyes using OCT, 18 (7%) using FAF, 27 (10%) eyes using mfERG, and 20 (7%) using MP.

MP had the lowest discrepancy between the overall number of eyes with abnormalities (72 [27%] of 266) detected and the number of eyes with abnormalities related to HCQ (20 [28%] of 72), followed by OCT (21% and 25%, respectively), FAF (19% and 35%) and mfERG (37% and 28%). Only four patients (3%) showed changes in all four tests suggestive of HCQ retinopathy.

Courtesy Syed Mahmood Ali Shah, MBBS, MD

In the absence of baseline data from the AAO recommended ancillary tests before the use of HCQ, “it may be difficult to interpret changes seen on these tests since most of the screenings are done by regular ophthalmologists who lack the equipment and experience with specialized testing such as mfERG, FAF, and OCT,” Dr. Shah and his coauthors noted. “We found a substantial number of cases with abnormalities unrelated to HCQ.”

Giving some practical advice, Dr. Shah noted that “before a patient starts treatment with HCQ, they should undergo a baseline ophthalmic assessment. Then if the patient complains of any vision changes, even if they have been taking the drug for less than 5 years, they should be reassessed.”

While repeat follow-up is, of course, necessary, he intimated that it is necessary to find a balance of risk and cost in regard to the frequency of screening for drug-related damage. “The American Academy of Ophthalmology currently recommends that a baseline fundus exam be performed shortly after starting HCQ. Ancillary OCT and visual fields shall only be performed if the fundus is abnormal at this baseline exam. However, since most retina specialists get OCT and visual field testing anyway it is wise to look at these as well,” he suggested. After 5 years of using the drug, they must be seen more regularly, and this is the point when ophthalmologists can decide if this should be every 6 months or annually, with the latter recommended by the AAO guidelines for patients with no additional risk factors.

The study was supported by noncommercial grants. Dr. Shah had no conflicts of interest to disclose.

LONDON – Retinopathy in patients taking long-term hydroxychloroquine for rheumatic conditions requires assessment by those experienced with specialized ophthalmic imaging, according to study findings presented at the European Congress of Rheumatology.

Nonspecific abnormalities, which often are unrelated to hydroxychloroquine (HCQ), can be seen with many of the tests recommended by current ophthalmology guidelines. These changes need “careful interpretation by retina specialists,” the study’s investigators wrote in a poster presentation.

HCQ is used widely for the treatment of systemic lupus erythematosus (SLE), rheumatoid arthritis, and many other inflammatory or autoimmune conditions, but it can cause irreversible eye damage and is often associated with prolonged (greater than 5 years) use. Specifically, it can cause a type of end-stage retinopathy called bull’s-eye maculopathy, which is where the fovea becomes hyperpigmented, much like the bull’s-eye on a dartboard. This can lead to substantial vision loss (blind spots) if not caught early.

Although it is reasonably rare to develop end-stage retinopathy, there is currently no treatment for HCQ-induced retinopathy. Stopping the drug may not necessarily stop the retinal damage, and drug withdrawal may not be an option in many patients given the lack of alternative options to treat the symptoms of SLE, study author and ophthalmologist Syed Mahmood Ali Shah, MBBS, MD, said in an interview.

Dr. Shah and his associates at Johns Hopkins University in Baltimore reported on applying the 2011 American Academy of Ophthalmology (AAO) guidelines on screening for HCQ retinopathy (Ophthalmology. 2011;118:415-22) to an academic practice. They also estimated the prevalence of HCQ retinopathy among 135 consecutively treated patients with SLE using recommended tests. The mean duration of HCQ use was 12.5 years.

The 2011 AAO guidelines – which in March 2016 were updated (Ophthalmology 2016 Jun;123:1386-94) – recommended the use of three “ancillary” tests in addition to the usual clinical ophthalmic examination and assessment of visual fields: optical coherence tomography (OCT), fundus autofluorescence (FAF), and multifocal electroretinography (mfERG). Dr. Shah and his colleagues used these three tests together with eye-tracking microperimetry (MP) as a substitute for Humphrey Visual Fields (HVF), which is a common visual field test used in the United States.

Courtesy Syed Mahmood Ali Shah, MBBS, MD

One difference between the 2011 guidelines and 2016 revision is that “the baseline exam can now be performed relying [only] on the fundus exam, with additional imaging required only for abnormal patients,” Dr. Shah said. “Overall, the guidelines have not changed on how often and how much you follow up,” he added. “The change is that there is no need to do these tests at baseline unless changes of the fundus are present.” However, OCT has become more widely used in many offices and has been recognized as the most useful objective test and shall be performed if there are any abnormal findings of the fundus.

A total of 266 eyes were examined using these imaging methods and interpreted by experienced retina specialists. Overall, HCQ-related abnormalities were noted in 14 (5%) eyes using OCT, 18 (7%) using FAF, 27 (10%) eyes using mfERG, and 20 (7%) using MP.

MP had the lowest discrepancy between the overall number of eyes with abnormalities (72 [27%] of 266) detected and the number of eyes with abnormalities related to HCQ (20 [28%] of 72), followed by OCT (21% and 25%, respectively), FAF (19% and 35%) and mfERG (37% and 28%). Only four patients (3%) showed changes in all four tests suggestive of HCQ retinopathy.

Courtesy Syed Mahmood Ali Shah, MBBS, MD

In the absence of baseline data from the AAO recommended ancillary tests before the use of HCQ, “it may be difficult to interpret changes seen on these tests since most of the screenings are done by regular ophthalmologists who lack the equipment and experience with specialized testing such as mfERG, FAF, and OCT,” Dr. Shah and his coauthors noted. “We found a substantial number of cases with abnormalities unrelated to HCQ.”

Giving some practical advice, Dr. Shah noted that “before a patient starts treatment with HCQ, they should undergo a baseline ophthalmic assessment. Then if the patient complains of any vision changes, even if they have been taking the drug for less than 5 years, they should be reassessed.”

While repeat follow-up is, of course, necessary, he intimated that it is necessary to find a balance of risk and cost in regard to the frequency of screening for drug-related damage. “The American Academy of Ophthalmology currently recommends that a baseline fundus exam be performed shortly after starting HCQ. Ancillary OCT and visual fields shall only be performed if the fundus is abnormal at this baseline exam. However, since most retina specialists get OCT and visual field testing anyway it is wise to look at these as well,” he suggested. After 5 years of using the drug, they must be seen more regularly, and this is the point when ophthalmologists can decide if this should be every 6 months or annually, with the latter recommended by the AAO guidelines for patients with no additional risk factors.

The study was supported by noncommercial grants. Dr. Shah had no conflicts of interest to disclose.

Among patients with immune-mediated diseases and a history of malignancy, cancer recurrence rates were similar regardless of whether they received tumor necrosis factor inhibitors, traditional immunosuppressants, or no immunosuppression, according to a meta-analysis of 16 cohort and case-control studies.

“However, there is a need for larger studies to prospectively monitor for cancer recurrence and new malignancies in this population to better inform our practice,” wrote Dr. Edward Shelton of Massachusetts General Hospital in Boston, and his associates. The report is in the July issue of Gastroenterology.

Patients with immune-mediated diseases often have a history of malignancy, raising questions about the effects of therapies that target the immune system, the researchers noted. However, relevant studies have been “small with few events, preventing robust estimates of risk,” they said. They searched Medline, Embase, and conference proceedings through April 2015 for studies of the risk of primary or recurrent cancer among patients with a history of malignancy who were exposed to thiopurines, methotrexate, or anti-TNF agents, or no immunosuppression. Among the 16 studies meeting these criteria, seven included patients with rheumatoid arthritis, seven included patients with inflammatory bowel disease, one included both diseases, and one included patients with psoriasis. Twelve were cohort studies, one was a case-control study, and three were case series. The resulting meta-analysis comprised 11,702 patients who contributed a total of 31,258 person-years of follow-up (Gastroenterology 2016 May 13. doi: 10.1053/j.gastro.2016.03.037).

Rates of cancer recurrence were statistically similar among patients who received no immunosuppression, anti-TNF therapy, traditional immune modulators, or combination regimens (P greater than .1 for differences among groups). Numerically, however, the risk of recurrent cancer was highest with combination immunotherapy (54.5 cases per 1,000 person-years of follow-up), compared with 37.5 cases per 1,000 person-years for patients who did not receive immunosuppressive treatment, 36.2 cases per 1,000 person-years for patients who received traditional immunomodulator monotherapy, and 33.8 cases per 1,000 person-years for patients who received anti-TNF agents. Analyses of subgroups of patients with new or recurrent cancers, or various types of therapies, and of specific immune-mediated diseases yielded “similar results, with no increase in risk,” said the researchers. Furthermore, rates of cancer recurrence did not statistically differ depending on whether patients started immunosuppression less than or more than 6 years after their index cancer (P = .43).

“Treatment decisions after a cancer diagnosis are complex, and must take into account the natural history of cancer, histologic type and stage, time from diagnosis, and course of underlying chronic inflammatory disease,” the researchers noted. “Our findings suggest that anti-TNF therapy, conventional immunosuppressant therapy, or combination immunosuppression are not associated with an increased risk of cancer recurrence in this population.”

The researchers cited several limitations. Notably, three of the studies included only 20 patients, and the studies included variable index cancers and methods for detecting recurrent cancers. “It also is possible, and likely, that patients who were at high risk for recurrence were not recommenced on immunosuppression, and consequently our findings may be more applicable to a population in which the patient and physicians were comfortable with re-initiation of therapy,” they said.

The National Institutes of Health supported several of the study investigators. Dr. Shelton had no disclosures. Five coinvestigators disclosed relationships with a number of pharmaceutical companies.

Among patients with immune-mediated diseases and a history of malignancy, cancer recurrence rates were similar regardless of whether they received tumor necrosis factor inhibitors, traditional immunosuppressants, or no immunosuppression, according to a meta-analysis of 16 cohort and case-control studies.

“However, there is a need for larger studies to prospectively monitor for cancer recurrence and new malignancies in this population to better inform our practice,” wrote Dr. Edward Shelton of Massachusetts General Hospital in Boston, and his associates. The report is in the July issue of Gastroenterology.

Patients with immune-mediated diseases often have a history of malignancy, raising questions about the effects of therapies that target the immune system, the researchers noted. However, relevant studies have been “small with few events, preventing robust estimates of risk,” they said. They searched Medline, Embase, and conference proceedings through April 2015 for studies of the risk of primary or recurrent cancer among patients with a history of malignancy who were exposed to thiopurines, methotrexate, or anti-TNF agents, or no immunosuppression. Among the 16 studies meeting these criteria, seven included patients with rheumatoid arthritis, seven included patients with inflammatory bowel disease, one included both diseases, and one included patients with psoriasis. Twelve were cohort studies, one was a case-control study, and three were case series. The resulting meta-analysis comprised 11,702 patients who contributed a total of 31,258 person-years of follow-up (Gastroenterology 2016 May 13. doi: 10.1053/j.gastro.2016.03.037).

Rates of cancer recurrence were statistically similar among patients who received no immunosuppression, anti-TNF therapy, traditional immune modulators, or combination regimens (P greater than .1 for differences among groups). Numerically, however, the risk of recurrent cancer was highest with combination immunotherapy (54.5 cases per 1,000 person-years of follow-up), compared with 37.5 cases per 1,000 person-years for patients who did not receive immunosuppressive treatment, 36.2 cases per 1,000 person-years for patients who received traditional immunomodulator monotherapy, and 33.8 cases per 1,000 person-years for patients who received anti-TNF agents. Analyses of subgroups of patients with new or recurrent cancers, or various types of therapies, and of specific immune-mediated diseases yielded “similar results, with no increase in risk,” said the researchers. Furthermore, rates of cancer recurrence did not statistically differ depending on whether patients started immunosuppression less than or more than 6 years after their index cancer (P = .43).

“Treatment decisions after a cancer diagnosis are complex, and must take into account the natural history of cancer, histologic type and stage, time from diagnosis, and course of underlying chronic inflammatory disease,” the researchers noted. “Our findings suggest that anti-TNF therapy, conventional immunosuppressant therapy, or combination immunosuppression are not associated with an increased risk of cancer recurrence in this population.”

The researchers cited several limitations. Notably, three of the studies included only 20 patients, and the studies included variable index cancers and methods for detecting recurrent cancers. “It also is possible, and likely, that patients who were at high risk for recurrence were not recommenced on immunosuppression, and consequently our findings may be more applicable to a population in which the patient and physicians were comfortable with re-initiation of therapy,” they said.

The National Institutes of Health supported several of the study investigators. Dr. Shelton had no disclosures. Five coinvestigators disclosed relationships with a number of pharmaceutical companies.

Among patients with immune-mediated diseases and a history of malignancy, cancer recurrence rates were similar regardless of whether they received tumor necrosis factor inhibitors, traditional immunosuppressants, or no immunosuppression, according to a meta-analysis of 16 cohort and case-control studies.

“However, there is a need for larger studies to prospectively monitor for cancer recurrence and new malignancies in this population to better inform our practice,” wrote Dr. Edward Shelton of Massachusetts General Hospital in Boston, and his associates. The report is in the July issue of Gastroenterology.

Patients with immune-mediated diseases often have a history of malignancy, raising questions about the effects of therapies that target the immune system, the researchers noted. However, relevant studies have been “small with few events, preventing robust estimates of risk,” they said. They searched Medline, Embase, and conference proceedings through April 2015 for studies of the risk of primary or recurrent cancer among patients with a history of malignancy who were exposed to thiopurines, methotrexate, or anti-TNF agents, or no immunosuppression. Among the 16 studies meeting these criteria, seven included patients with rheumatoid arthritis, seven included patients with inflammatory bowel disease, one included both diseases, and one included patients with psoriasis. Twelve were cohort studies, one was a case-control study, and three were case series. The resulting meta-analysis comprised 11,702 patients who contributed a total of 31,258 person-years of follow-up (Gastroenterology 2016 May 13. doi: 10.1053/j.gastro.2016.03.037).

Rates of cancer recurrence were statistically similar among patients who received no immunosuppression, anti-TNF therapy, traditional immune modulators, or combination regimens (P greater than .1 for differences among groups). Numerically, however, the risk of recurrent cancer was highest with combination immunotherapy (54.5 cases per 1,000 person-years of follow-up), compared with 37.5 cases per 1,000 person-years for patients who did not receive immunosuppressive treatment, 36.2 cases per 1,000 person-years for patients who received traditional immunomodulator monotherapy, and 33.8 cases per 1,000 person-years for patients who received anti-TNF agents. Analyses of subgroups of patients with new or recurrent cancers, or various types of therapies, and of specific immune-mediated diseases yielded “similar results, with no increase in risk,” said the researchers. Furthermore, rates of cancer recurrence did not statistically differ depending on whether patients started immunosuppression less than or more than 6 years after their index cancer (P = .43).

“Treatment decisions after a cancer diagnosis are complex, and must take into account the natural history of cancer, histologic type and stage, time from diagnosis, and course of underlying chronic inflammatory disease,” the researchers noted. “Our findings suggest that anti-TNF therapy, conventional immunosuppressant therapy, or combination immunosuppression are not associated with an increased risk of cancer recurrence in this population.”

The researchers cited several limitations. Notably, three of the studies included only 20 patients, and the studies included variable index cancers and methods for detecting recurrent cancers. “It also is possible, and likely, that patients who were at high risk for recurrence were not recommenced on immunosuppression, and consequently our findings may be more applicable to a population in which the patient and physicians were comfortable with re-initiation of therapy,” they said.

The National Institutes of Health supported several of the study investigators. Dr. Shelton had no disclosures. Five coinvestigators disclosed relationships with a number of pharmaceutical companies.

LONDON – A single, intravenous infusion of 1,000 mg of rituximab to people with arthralgia and a high risk for developing rheumatoid arthritis cut the subsequent rate of rheumatoid arthritis development roughly in half during more than 18 months of follow-up in a proof-of-concept, placebo-controlled study that randomized 81 people.

“This is the first study to evaluate the effects of a biopharmaceutical in subjects at risk of developing RA [rheumatoid arthritis],” Dr. Daniëlle M. Gerlag said at the European Congress of Rheumatology. “These results strongly support the rationale for future clinical trials aimed at prevention of RA by a targeted intervention,” added Dr. Gerlag, a rheumatologist at the Academic Medical Center in Amsterdam.

Mitchel L. Zoler/Frontline Medical News

Additional studies are needed to confirm this effect and to examine whether the period of protection against RA development can be extended by administration of additional rituximab (Rituxan) doses. In the current study, the protective effect from the single dose administered appeared to wane over time, she noted.

The idea behind this strategy is that a window of opportunity exists in people at high risk for developing RA to prevent the disease by blocking production of the autoantibodies that trigger the development of a subclinical synovitis that eventually leads to RA. Rituximab is a cytolytic antibody directed against the CD20 antigen on B cells that already has regulatory approval for treating moderately to severely active RA as well as certain other diseases.

Dr. Gerlag and her associates recently published an analysis that detailed their rationale for hypothesizing that prophylactic treatment with rituximab might prove effective at delaying or preventing the development of RA in susceptible people (Rheumatology [Oxford]. 2016 April;55[4]:607-14).

The Prevention of RA by Rituximab (PRAIRI) study ran at three Dutch centers. The investigators enrolled people with arthralgia who had never been diagnosed with arthritis, had never used a disease-modifying antirheumatic drug, and had at least one of these two risk factors: a serum level of IgM rheumatoid factor of more than 12.5 IU/mL and a serum level of anticitrullinated peptide antibodies of more than 25 IU/mL. Enrolled participants also needed to have at least one of the following: a serum level of C-reactive protein greater than 3 mg/L, an erythrocyte sedimentation rate of greater than 28 mm/hr, and evidence of subclinical synovitis identified by either ultrasound or MRI.

The researchers found these participants largely through screening sessions run at health fairs and by publicizing the study during television appearances, Dr. Gerlag said. About three-quarters of the participants were first-degree relatives of patients already diagnosed with RA, but this was not a criterion for enrollment. The participants averaged about 53 years old, and nearly two-thirds were women.

Among the 81 people who underwent treatment, 41 received a single, 1,000-mg infusion of rituximab, and 40 received a placebo infusion. The researchers then followed the participants with scheduled, periodic examinations during a median of 29 months.

During follow-up, 16 of the 40 people in the placebo group (40%) developed RA after a median of 12 months, and 14 of the 41 in the treated arm (34%) developed RA after a median of 17 months.

The researchers performed two different statistical analyses on these outcomes. They used a Kaplan-Meier survival analysis to determine the time until 25% of people in each arm developed RA. Among the placebo patients, this occurred after 12 months, while in the intervention arm, it did not occur until 24 months, a statistically significant doubling of the time to this outcome with rituximab treatment, Dr. Gerlag reported.

The second analysis calculated a Cox proportional hazard ratio based on the time to development of rheumatoid arthritis among those in each of the treatment groups. This determined a 55% reduced hazard ratio after 12 months among people treated with rituximab, compared with the placebo-treated controls, and a 53% reduced hazard after 18 months, both statistically significant differences.

A safety analysis showed that some people treated with rituximab had mild infusion-related symptoms, but no participants had serious infections. Serious adverse events occurred in 11 people in the rituximab group and in 3 in the placebo arm, but none of these serious adverse events was judged to be related to treatment by the study’s data safety monitoring board, said Dr. Gerlag, who is also on the staff of GlaxoSmithKline in Cambridge, England.

The PRAIRI study received no commercial funding. Dr. Gerlag is also a shareholder in GlaxoSmithKline, but the company played no role in the study.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

LONDON – A single, intravenous infusion of 1,000 mg of rituximab to people with arthralgia and a high risk for developing rheumatoid arthritis cut the subsequent rate of rheumatoid arthritis development roughly in half during more than 18 months of follow-up in a proof-of-concept, placebo-controlled study that randomized 81 people.

“This is the first study to evaluate the effects of a biopharmaceutical in subjects at risk of developing RA [rheumatoid arthritis],” Dr. Daniëlle M. Gerlag said at the European Congress of Rheumatology. “These results strongly support the rationale for future clinical trials aimed at prevention of RA by a targeted intervention,” added Dr. Gerlag, a rheumatologist at the Academic Medical Center in Amsterdam.

Mitchel L. Zoler/Frontline Medical News

Additional studies are needed to confirm this effect and to examine whether the period of protection against RA development can be extended by administration of additional rituximab (Rituxan) doses. In the current study, the protective effect from the single dose administered appeared to wane over time, she noted.

The idea behind this strategy is that a window of opportunity exists in people at high risk for developing RA to prevent the disease by blocking production of the autoantibodies that trigger the development of a subclinical synovitis that eventually leads to RA. Rituximab is a cytolytic antibody directed against the CD20 antigen on B cells that already has regulatory approval for treating moderately to severely active RA as well as certain other diseases.

Dr. Gerlag and her associates recently published an analysis that detailed their rationale for hypothesizing that prophylactic treatment with rituximab might prove effective at delaying or preventing the development of RA in susceptible people (Rheumatology [Oxford]. 2016 April;55[4]:607-14).

The Prevention of RA by Rituximab (PRAIRI) study ran at three Dutch centers. The investigators enrolled people with arthralgia who had never been diagnosed with arthritis, had never used a disease-modifying antirheumatic drug, and had at least one of these two risk factors: a serum level of IgM rheumatoid factor of more than 12.5 IU/mL and a serum level of anticitrullinated peptide antibodies of more than 25 IU/mL. Enrolled participants also needed to have at least one of the following: a serum level of C-reactive protein greater than 3 mg/L, an erythrocyte sedimentation rate of greater than 28 mm/hr, and evidence of subclinical synovitis identified by either ultrasound or MRI.

The researchers found these participants largely through screening sessions run at health fairs and by publicizing the study during television appearances, Dr. Gerlag said. About three-quarters of the participants were first-degree relatives of patients already diagnosed with RA, but this was not a criterion for enrollment. The participants averaged about 53 years old, and nearly two-thirds were women.

Among the 81 people who underwent treatment, 41 received a single, 1,000-mg infusion of rituximab, and 40 received a placebo infusion. The researchers then followed the participants with scheduled, periodic examinations during a median of 29 months.

During follow-up, 16 of the 40 people in the placebo group (40%) developed RA after a median of 12 months, and 14 of the 41 in the treated arm (34%) developed RA after a median of 17 months.

The researchers performed two different statistical analyses on these outcomes. They used a Kaplan-Meier survival analysis to determine the time until 25% of people in each arm developed RA. Among the placebo patients, this occurred after 12 months, while in the intervention arm, it did not occur until 24 months, a statistically significant doubling of the time to this outcome with rituximab treatment, Dr. Gerlag reported.

The second analysis calculated a Cox proportional hazard ratio based on the time to development of rheumatoid arthritis among those in each of the treatment groups. This determined a 55% reduced hazard ratio after 12 months among people treated with rituximab, compared with the placebo-treated controls, and a 53% reduced hazard after 18 months, both statistically significant differences.

A safety analysis showed that some people treated with rituximab had mild infusion-related symptoms, but no participants had serious infections. Serious adverse events occurred in 11 people in the rituximab group and in 3 in the placebo arm, but none of these serious adverse events was judged to be related to treatment by the study’s data safety monitoring board, said Dr. Gerlag, who is also on the staff of GlaxoSmithKline in Cambridge, England.

The PRAIRI study received no commercial funding. Dr. Gerlag is also a shareholder in GlaxoSmithKline, but the company played no role in the study.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

LONDON – A single, intravenous infusion of 1,000 mg of rituximab to people with arthralgia and a high risk for developing rheumatoid arthritis cut the subsequent rate of rheumatoid arthritis development roughly in half during more than 18 months of follow-up in a proof-of-concept, placebo-controlled study that randomized 81 people.

“This is the first study to evaluate the effects of a biopharmaceutical in subjects at risk of developing RA [rheumatoid arthritis],” Dr. Daniëlle M. Gerlag said at the European Congress of Rheumatology. “These results strongly support the rationale for future clinical trials aimed at prevention of RA by a targeted intervention,” added Dr. Gerlag, a rheumatologist at the Academic Medical Center in Amsterdam.

Mitchel L. Zoler/Frontline Medical News

Additional studies are needed to confirm this effect and to examine whether the period of protection against RA development can be extended by administration of additional rituximab (Rituxan) doses. In the current study, the protective effect from the single dose administered appeared to wane over time, she noted.

The idea behind this strategy is that a window of opportunity exists in people at high risk for developing RA to prevent the disease by blocking production of the autoantibodies that trigger the development of a subclinical synovitis that eventually leads to RA. Rituximab is a cytolytic antibody directed against the CD20 antigen on B cells that already has regulatory approval for treating moderately to severely active RA as well as certain other diseases.

Dr. Gerlag and her associates recently published an analysis that detailed their rationale for hypothesizing that prophylactic treatment with rituximab might prove effective at delaying or preventing the development of RA in susceptible people (Rheumatology [Oxford]. 2016 April;55[4]:607-14).

The Prevention of RA by Rituximab (PRAIRI) study ran at three Dutch centers. The investigators enrolled people with arthralgia who had never been diagnosed with arthritis, had never used a disease-modifying antirheumatic drug, and had at least one of these two risk factors: a serum level of IgM rheumatoid factor of more than 12.5 IU/mL and a serum level of anticitrullinated peptide antibodies of more than 25 IU/mL. Enrolled participants also needed to have at least one of the following: a serum level of C-reactive protein greater than 3 mg/L, an erythrocyte sedimentation rate of greater than 28 mm/hr, and evidence of subclinical synovitis identified by either ultrasound or MRI.

The researchers found these participants largely through screening sessions run at health fairs and by publicizing the study during television appearances, Dr. Gerlag said. About three-quarters of the participants were first-degree relatives of patients already diagnosed with RA, but this was not a criterion for enrollment. The participants averaged about 53 years old, and nearly two-thirds were women.

Among the 81 people who underwent treatment, 41 received a single, 1,000-mg infusion of rituximab, and 40 received a placebo infusion. The researchers then followed the participants with scheduled, periodic examinations during a median of 29 months.

During follow-up, 16 of the 40 people in the placebo group (40%) developed RA after a median of 12 months, and 14 of the 41 in the treated arm (34%) developed RA after a median of 17 months.

The researchers performed two different statistical analyses on these outcomes. They used a Kaplan-Meier survival analysis to determine the time until 25% of people in each arm developed RA. Among the placebo patients, this occurred after 12 months, while in the intervention arm, it did not occur until 24 months, a statistically significant doubling of the time to this outcome with rituximab treatment, Dr. Gerlag reported.

The second analysis calculated a Cox proportional hazard ratio based on the time to development of rheumatoid arthritis among those in each of the treatment groups. This determined a 55% reduced hazard ratio after 12 months among people treated with rituximab, compared with the placebo-treated controls, and a 53% reduced hazard after 18 months, both statistically significant differences.

A safety analysis showed that some people treated with rituximab had mild infusion-related symptoms, but no participants had serious infections. Serious adverse events occurred in 11 people in the rituximab group and in 3 in the placebo arm, but none of these serious adverse events was judged to be related to treatment by the study’s data safety monitoring board, said Dr. Gerlag, who is also on the staff of GlaxoSmithKline in Cambridge, England.

The PRAIRI study received no commercial funding. Dr. Gerlag is also a shareholder in GlaxoSmithKline, but the company played no role in the study.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

LONDON – Subcutaneous methotrexate monotherapy may be more effective at helping recently diagnosed patients with rheumatoid arthritis avoid biologic therapy, compared with similar patients on oral methotrexate, based on an analysis of data collected from 483 Canadian patients in routine care and enrolled in a national registry.

“This is a signal for improved efficacy with subcutaneous methotrexate, compared with oral methotrexate,” said Dr. Stephanie Gottheil, who reported these results at the European Congress of Rheumatology.

“In general, as long as patients with rheumatoid arthritis are under good control without a biologic drug, that is preferable” to initiating biologic treatment, said Dr. Gottheil, a researcher at Western University in London, Ont. Delaying the start of biologic treatment saves money, avoids the increased risk of infection that comes with biologic treatment, and defers a patient’s immune response to a biologic drug that can eventually compromise the biologic’s efficacy, she said in an interview.

“These data did not come from a randomized trial and so are by no means conclusive, but this is a signal that supports other data that subcutaneous methotrexate potentially puts patients into remission faster, and we know that earlier remission predicts more sustained remission,” she said.

“The biggest barrier to subcutaneous administration of methotrexate is patient preference to not inject themselves, but results from some studies have also shown that subcutaneous methotrexate is better tolerated,” compared with oral dosing, she added.

The study used data collected in the Canadian Early Arthritis Cohort (CATCH), which enrolls patients at several centers throughout Canada diagnosed with rheumatoid arthritis for less than 12 months. Dr. Gottheil and her associates particularly focused on 1,189 early RA patients with moderate to severe disease activity enrolled in CATCH during 2007-2012 who received methotrexate and had never previously received a biologic drug. The study’s primary endpoint was time to first treatment with a biologic during 3 years of follow-up after entry into the registry.

The patients’ average age at enrollment was 56 years, more than two-thirds were women, and their average methotrexate dosage was 20 mg/week. The cohort included 483 patients on methotrexate monotherapy – with virtually equal numbers on oral methotrexate and subcutaneous methotrexate – and 706 on a regimen that combined methotrexate with one or more additional (nonbiologic) drugs at baseline. The patients in each of the methotrexate monotherapy subgroups, those on oral or subcutaneous therapy, were very similar in their demographic and clinical profiles.

The analysis showed no statistically significant difference in time to first biologic use between the patients on a combination regimen and those on oral methotrexate monotherapy.

But when the researchers compared the time to first biologic among those on subcutaneous methotrexate monotherapy with those on oral methotrexate monotherapy, the subcutaneous patients showed a statistically significant, 47% reduced rate of starting any biologic drug during follow-up in an analysis that controlled for age, sex, education, comorbidities, disease duration, baseline disease activity, baseline corticosteroid use, joint erosions at baseline, and score on the health-assessment questionnaire at baseline, Dr. Gottheil reported.

The analysis also revealed three other variables that significantly linked with a slower progression to biologic treatment: older age, no use of corticosteroid treatment at baseline, and lower disease activity at baseline.

The CATCH registry research program is sponsored by AbbVie, Amgen, Bristol-Myers Squibb, Hoffmann-La Roche, Janssen, Pfizer, and UCB. Dr. Gottheil had no relevant disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – Subcutaneous methotrexate monotherapy may be more effective at helping recently diagnosed patients with rheumatoid arthritis avoid biologic therapy, compared with similar patients on oral methotrexate, based on an analysis of data collected from 483 Canadian patients in routine care and enrolled in a national registry.

“This is a signal for improved efficacy with subcutaneous methotrexate, compared with oral methotrexate,” said Dr. Stephanie Gottheil, who reported these results at the European Congress of Rheumatology.

“In general, as long as patients with rheumatoid arthritis are under good control without a biologic drug, that is preferable” to initiating biologic treatment, said Dr. Gottheil, a researcher at Western University in London, Ont. Delaying the start of biologic treatment saves money, avoids the increased risk of infection that comes with biologic treatment, and defers a patient’s immune response to a biologic drug that can eventually compromise the biologic’s efficacy, she said in an interview.

“These data did not come from a randomized trial and so are by no means conclusive, but this is a signal that supports other data that subcutaneous methotrexate potentially puts patients into remission faster, and we know that earlier remission predicts more sustained remission,” she said.

“The biggest barrier to subcutaneous administration of methotrexate is patient preference to not inject themselves, but results from some studies have also shown that subcutaneous methotrexate is better tolerated,” compared with oral dosing, she added.

The study used data collected in the Canadian Early Arthritis Cohort (CATCH), which enrolls patients at several centers throughout Canada diagnosed with rheumatoid arthritis for less than 12 months. Dr. Gottheil and her associates particularly focused on 1,189 early RA patients with moderate to severe disease activity enrolled in CATCH during 2007-2012 who received methotrexate and had never previously received a biologic drug. The study’s primary endpoint was time to first treatment with a biologic during 3 years of follow-up after entry into the registry.

The patients’ average age at enrollment was 56 years, more than two-thirds were women, and their average methotrexate dosage was 20 mg/week. The cohort included 483 patients on methotrexate monotherapy – with virtually equal numbers on oral methotrexate and subcutaneous methotrexate – and 706 on a regimen that combined methotrexate with one or more additional (nonbiologic) drugs at baseline. The patients in each of the methotrexate monotherapy subgroups, those on oral or subcutaneous therapy, were very similar in their demographic and clinical profiles.

The analysis showed no statistically significant difference in time to first biologic use between the patients on a combination regimen and those on oral methotrexate monotherapy.

But when the researchers compared the time to first biologic among those on subcutaneous methotrexate monotherapy with those on oral methotrexate monotherapy, the subcutaneous patients showed a statistically significant, 47% reduced rate of starting any biologic drug during follow-up in an analysis that controlled for age, sex, education, comorbidities, disease duration, baseline disease activity, baseline corticosteroid use, joint erosions at baseline, and score on the health-assessment questionnaire at baseline, Dr. Gottheil reported.

The analysis also revealed three other variables that significantly linked with a slower progression to biologic treatment: older age, no use of corticosteroid treatment at baseline, and lower disease activity at baseline.

The CATCH registry research program is sponsored by AbbVie, Amgen, Bristol-Myers Squibb, Hoffmann-La Roche, Janssen, Pfizer, and UCB. Dr. Gottheil had no relevant disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – Subcutaneous methotrexate monotherapy may be more effective at helping recently diagnosed patients with rheumatoid arthritis avoid biologic therapy, compared with similar patients on oral methotrexate, based on an analysis of data collected from 483 Canadian patients in routine care and enrolled in a national registry.

“This is a signal for improved efficacy with subcutaneous methotrexate, compared with oral methotrexate,” said Dr. Stephanie Gottheil, who reported these results at the European Congress of Rheumatology.

“In general, as long as patients with rheumatoid arthritis are under good control without a biologic drug, that is preferable” to initiating biologic treatment, said Dr. Gottheil, a researcher at Western University in London, Ont. Delaying the start of biologic treatment saves money, avoids the increased risk of infection that comes with biologic treatment, and defers a patient’s immune response to a biologic drug that can eventually compromise the biologic’s efficacy, she said in an interview.

“These data did not come from a randomized trial and so are by no means conclusive, but this is a signal that supports other data that subcutaneous methotrexate potentially puts patients into remission faster, and we know that earlier remission predicts more sustained remission,” she said.

“The biggest barrier to subcutaneous administration of methotrexate is patient preference to not inject themselves, but results from some studies have also shown that subcutaneous methotrexate is better tolerated,” compared with oral dosing, she added.

The study used data collected in the Canadian Early Arthritis Cohort (CATCH), which enrolls patients at several centers throughout Canada diagnosed with rheumatoid arthritis for less than 12 months. Dr. Gottheil and her associates particularly focused on 1,189 early RA patients with moderate to severe disease activity enrolled in CATCH during 2007-2012 who received methotrexate and had never previously received a biologic drug. The study’s primary endpoint was time to first treatment with a biologic during 3 years of follow-up after entry into the registry.

The patients’ average age at enrollment was 56 years, more than two-thirds were women, and their average methotrexate dosage was 20 mg/week. The cohort included 483 patients on methotrexate monotherapy – with virtually equal numbers on oral methotrexate and subcutaneous methotrexate – and 706 on a regimen that combined methotrexate with one or more additional (nonbiologic) drugs at baseline. The patients in each of the methotrexate monotherapy subgroups, those on oral or subcutaneous therapy, were very similar in their demographic and clinical profiles.

The analysis showed no statistically significant difference in time to first biologic use between the patients on a combination regimen and those on oral methotrexate monotherapy.

But when the researchers compared the time to first biologic among those on subcutaneous methotrexate monotherapy with those on oral methotrexate monotherapy, the subcutaneous patients showed a statistically significant, 47% reduced rate of starting any biologic drug during follow-up in an analysis that controlled for age, sex, education, comorbidities, disease duration, baseline disease activity, baseline corticosteroid use, joint erosions at baseline, and score on the health-assessment questionnaire at baseline, Dr. Gottheil reported.

The analysis also revealed three other variables that significantly linked with a slower progression to biologic treatment: older age, no use of corticosteroid treatment at baseline, and lower disease activity at baseline.

The CATCH registry research program is sponsored by AbbVie, Amgen, Bristol-Myers Squibb, Hoffmann-La Roche, Janssen, Pfizer, and UCB. Dr. Gottheil had no relevant disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler