Rheumatoid Arthritis

MADRID – Having a child was associated with ACPA-negative but not ACPA-positive rheumatoid arthritis in a case-control study of almost 5,000 women living in Sweden.

The odds ratio (OR) for ACPA (anti–citrullinated protein antibody)–negative rheumatoid arthritis (RA) comparing parous with nulliparous women was 2.1 in women aged 18-44 years. The effect was not seen in older women, with an OR of 0.9 for women aged 45-70 years.

"The risk seems to be more pronounced in the postpartum period [in the] 2 years before the onset of [RA] symptoms," Cecilia Orellana reported at the annual European Congress of Rheumatology. Indeed, the odds of developing ACPA-positive disease within the first year of childbirth (OR = 2.6) was higher than within 2 years (OR = 1.8).

Ms. Orellana, a second-year postgraduate student within the Institute of Environmental Medicine at the Karolinska Institutet in Stockholm, also noted that the risk of ACPA-negative RA appeared higher in women who had their first child at a young age. The OR for ACPA-negative RA in women younger than 23 years was 2.5, followed by 2.1 for those aged 23-26 years, 1.8 for those aged 27-30 years, and 1.5 for those older than 30 years.

The link between parity and RA has been studied before with some findings suggesting no association and others finding a possible protective effect of parity on the risk of RA. This is the only study to date to look at parity in relation to ACPA status (Ann. Rheum. Dis. 2013;72[Suppl. 3]:102).

The case-control study involved 2,035 women with RA and 2,911 age-matched controls enrolled in the ongoing Swedish EIRA (Epidemiological Investigation of RA) study during 1996-2009. Nearly two-thirds (64%) of women with RA were ACPA positive.

ORs were adjusted for smoking status, education, body mass index, age of menarche, and oral contraceptive use, but none of these adjustments altered the risk of developing RA.

The biological mechanisms behind the increased risk for ACPA-negative RA in women who have given birth needs further study, Ms. Orellana concluded.

The findings appear "counterintuitive" to what clinicians might assume, Dr. Christopher Buckley, professor of rheumatology at the University of Birmingham, England, said in an interview.

"I would have predicted that if women had had more children, there might have been more [ACPA-positive] disease, because you are more likely to have immune suppression, but this [study] actually suggests that women are protected from [ACPA-positive] disease," said Dr. Buckley, who was not involved in the study. "This might mean that pregnancy is not a bad thing," he said, adding that if women do get pregnant they are more likely to have ACPA-negative disease, which actually carries a better prognosis.

As for how these data could help clinicians advise women, Dr. Buckley noted that it is of course very likely that there is more than a single factor at play. Other factors would almost certainly be influencing the risk of RA. But these data beg the question as to how many children a woman might need to have to produce an effect. Since parity seems to influence ACPA-negative RA risk in younger women, the findings might be most relevant in the developing world where women tend to have their children at a younger age.

"It’s one of those results that is completely counterintuitive," Dr. Buckley said, "which usually tells you that there is something going on."

Ms. Orellana and Dr. Buckley had no disclosures. The study was supported by grants from the Swedish Medical Research Council, the Swedish Council for Working Life and Social Research, King Gustav V’s 80-year Foundation, the Swedish Rheumatic Foundation, the Stockholm County Council, and the insurance company AFA.

MADRID – Having a child was associated with ACPA-negative but not ACPA-positive rheumatoid arthritis in a case-control study of almost 5,000 women living in Sweden.

The odds ratio (OR) for ACPA (anti–citrullinated protein antibody)–negative rheumatoid arthritis (RA) comparing parous with nulliparous women was 2.1 in women aged 18-44 years. The effect was not seen in older women, with an OR of 0.9 for women aged 45-70 years.

"The risk seems to be more pronounced in the postpartum period [in the] 2 years before the onset of [RA] symptoms," Cecilia Orellana reported at the annual European Congress of Rheumatology. Indeed, the odds of developing ACPA-positive disease within the first year of childbirth (OR = 2.6) was higher than within 2 years (OR = 1.8).

Ms. Orellana, a second-year postgraduate student within the Institute of Environmental Medicine at the Karolinska Institutet in Stockholm, also noted that the risk of ACPA-negative RA appeared higher in women who had their first child at a young age. The OR for ACPA-negative RA in women younger than 23 years was 2.5, followed by 2.1 for those aged 23-26 years, 1.8 for those aged 27-30 years, and 1.5 for those older than 30 years.

The link between parity and RA has been studied before with some findings suggesting no association and others finding a possible protective effect of parity on the risk of RA. This is the only study to date to look at parity in relation to ACPA status (Ann. Rheum. Dis. 2013;72[Suppl. 3]:102).

The case-control study involved 2,035 women with RA and 2,911 age-matched controls enrolled in the ongoing Swedish EIRA (Epidemiological Investigation of RA) study during 1996-2009. Nearly two-thirds (64%) of women with RA were ACPA positive.

ORs were adjusted for smoking status, education, body mass index, age of menarche, and oral contraceptive use, but none of these adjustments altered the risk of developing RA.

The biological mechanisms behind the increased risk for ACPA-negative RA in women who have given birth needs further study, Ms. Orellana concluded.

The findings appear "counterintuitive" to what clinicians might assume, Dr. Christopher Buckley, professor of rheumatology at the University of Birmingham, England, said in an interview.

"I would have predicted that if women had had more children, there might have been more [ACPA-positive] disease, because you are more likely to have immune suppression, but this [study] actually suggests that women are protected from [ACPA-positive] disease," said Dr. Buckley, who was not involved in the study. "This might mean that pregnancy is not a bad thing," he said, adding that if women do get pregnant they are more likely to have ACPA-negative disease, which actually carries a better prognosis.

As for how these data could help clinicians advise women, Dr. Buckley noted that it is of course very likely that there is more than a single factor at play. Other factors would almost certainly be influencing the risk of RA. But these data beg the question as to how many children a woman might need to have to produce an effect. Since parity seems to influence ACPA-negative RA risk in younger women, the findings might be most relevant in the developing world where women tend to have their children at a younger age.

"It’s one of those results that is completely counterintuitive," Dr. Buckley said, "which usually tells you that there is something going on."

Ms. Orellana and Dr. Buckley had no disclosures. The study was supported by grants from the Swedish Medical Research Council, the Swedish Council for Working Life and Social Research, King Gustav V’s 80-year Foundation, the Swedish Rheumatic Foundation, the Stockholm County Council, and the insurance company AFA.

MADRID – Having a child was associated with ACPA-negative but not ACPA-positive rheumatoid arthritis in a case-control study of almost 5,000 women living in Sweden.

The odds ratio (OR) for ACPA (anti–citrullinated protein antibody)–negative rheumatoid arthritis (RA) comparing parous with nulliparous women was 2.1 in women aged 18-44 years. The effect was not seen in older women, with an OR of 0.9 for women aged 45-70 years.

"The risk seems to be more pronounced in the postpartum period [in the] 2 years before the onset of [RA] symptoms," Cecilia Orellana reported at the annual European Congress of Rheumatology. Indeed, the odds of developing ACPA-positive disease within the first year of childbirth (OR = 2.6) was higher than within 2 years (OR = 1.8).

Ms. Orellana, a second-year postgraduate student within the Institute of Environmental Medicine at the Karolinska Institutet in Stockholm, also noted that the risk of ACPA-negative RA appeared higher in women who had their first child at a young age. The OR for ACPA-negative RA in women younger than 23 years was 2.5, followed by 2.1 for those aged 23-26 years, 1.8 for those aged 27-30 years, and 1.5 for those older than 30 years.

The link between parity and RA has been studied before with some findings suggesting no association and others finding a possible protective effect of parity on the risk of RA. This is the only study to date to look at parity in relation to ACPA status (Ann. Rheum. Dis. 2013;72[Suppl. 3]:102).

The case-control study involved 2,035 women with RA and 2,911 age-matched controls enrolled in the ongoing Swedish EIRA (Epidemiological Investigation of RA) study during 1996-2009. Nearly two-thirds (64%) of women with RA were ACPA positive.

ORs were adjusted for smoking status, education, body mass index, age of menarche, and oral contraceptive use, but none of these adjustments altered the risk of developing RA.

The biological mechanisms behind the increased risk for ACPA-negative RA in women who have given birth needs further study, Ms. Orellana concluded.

The findings appear "counterintuitive" to what clinicians might assume, Dr. Christopher Buckley, professor of rheumatology at the University of Birmingham, England, said in an interview.

"I would have predicted that if women had had more children, there might have been more [ACPA-positive] disease, because you are more likely to have immune suppression, but this [study] actually suggests that women are protected from [ACPA-positive] disease," said Dr. Buckley, who was not involved in the study. "This might mean that pregnancy is not a bad thing," he said, adding that if women do get pregnant they are more likely to have ACPA-negative disease, which actually carries a better prognosis.

As for how these data could help clinicians advise women, Dr. Buckley noted that it is of course very likely that there is more than a single factor at play. Other factors would almost certainly be influencing the risk of RA. But these data beg the question as to how many children a woman might need to have to produce an effect. Since parity seems to influence ACPA-negative RA risk in younger women, the findings might be most relevant in the developing world where women tend to have their children at a younger age.

"It’s one of those results that is completely counterintuitive," Dr. Buckley said, "which usually tells you that there is something going on."

Ms. Orellana and Dr. Buckley had no disclosures. The study was supported by grants from the Swedish Medical Research Council, the Swedish Council for Working Life and Social Research, King Gustav V’s 80-year Foundation, the Swedish Rheumatic Foundation, the Stockholm County Council, and the insurance company AFA.

MADRID – Drug-free remission is possible for rheumatoid arthritis patients with anticitrullinated protein antibodies, although they may not be able to sustain it for as long as ACPA-negative patients.

Still, after treatment with methotrexate and tapered prednisone, more than one-third of ACPA-positive patients experienced drug-free remission for at least some period of time, Dr. Kirsten Wevers-de Boer said at the annual European Congress of Rheumatology.

"With this treatment strategy, the presence of ACPA appears not to preclude drug discontinuation," said Dr. Wevers-de Boer of the department of rheumatology at Leiden University Medical Center in the Netherlands.

She and her colleagues conducted a subanalysis of patients who achieved remission in the IMPROVED study, which examined remission rates in 610 patients with recent-onset rheumatoid or undifferentiated arthritis. They were treated with a two-step regimen of 7 weeks of methotrexate 25 mg/week along with a tapered course of prednisone. Prednisone was started at 60 mg/day and tapered to 7.5 mg/day by the end of the treatment period (Ann. Rheum. Dis. 2013 May 28 [doi:10.1136/annrheumdis-2013-203243]).

Patients not in remission 4 months after the treatment cycle were randomized to either one of two regimens – methotrexate, hydroxychloroquine, sulfasalazine, and low-dose prednisone, or methotrexate plus adalimumab.

Dr. Wevers-de Boer’s subanalysis focused on the 375 patients (61%) who achieved early drug-free remission. They were followed for up to 16 months.

At 1 year, 119 (32%) had remained in drug-free remission. Significantly more of the patients who were in drug-free remission at 1 year were ACPA negative than were those who were not in remission (62% vs. 50%).

At 16 months, 77 patients (65% of the entire group) were still in drug-free remission. Again, ACPA negativity was more often present among those who were still in drug-free remission than it was in those who were not in remission (80% vs. 58%).

Dr. Wevers-de Boer conducted regression analyses to look for any significant baseline factors that might predict the inability to sustain drug-free remission.

In the univariate analysis, significant factors were a high tender joint count at baseline, being ACPA-positive, and fulfilling the 2010 American College of Rheumatology-European League Against Rheumatism diagnostic criteria. In the multivariate analysis, the combination of high tender joint count and meeting the 2010 diagnostic criteria was significantly associated with an inability to sustain remission.

"Patients who are ACPA positive can achieve drug-free remission almost as often as patients who are ACPA negative, although they are somewhat less often able to sustain that," she said.

Dr. Wevers-de Boer disclosed that she has received grant funding from Abbott, which sponsored the IMPROVED study.

msullivan@frontlinemedcom.com

MADRID – Drug-free remission is possible for rheumatoid arthritis patients with anticitrullinated protein antibodies, although they may not be able to sustain it for as long as ACPA-negative patients.

Still, after treatment with methotrexate and tapered prednisone, more than one-third of ACPA-positive patients experienced drug-free remission for at least some period of time, Dr. Kirsten Wevers-de Boer said at the annual European Congress of Rheumatology.

"With this treatment strategy, the presence of ACPA appears not to preclude drug discontinuation," said Dr. Wevers-de Boer of the department of rheumatology at Leiden University Medical Center in the Netherlands.

She and her colleagues conducted a subanalysis of patients who achieved remission in the IMPROVED study, which examined remission rates in 610 patients with recent-onset rheumatoid or undifferentiated arthritis. They were treated with a two-step regimen of 7 weeks of methotrexate 25 mg/week along with a tapered course of prednisone. Prednisone was started at 60 mg/day and tapered to 7.5 mg/day by the end of the treatment period (Ann. Rheum. Dis. 2013 May 28 [doi:10.1136/annrheumdis-2013-203243]).

Patients not in remission 4 months after the treatment cycle were randomized to either one of two regimens – methotrexate, hydroxychloroquine, sulfasalazine, and low-dose prednisone, or methotrexate plus adalimumab.

Dr. Wevers-de Boer’s subanalysis focused on the 375 patients (61%) who achieved early drug-free remission. They were followed for up to 16 months.

At 1 year, 119 (32%) had remained in drug-free remission. Significantly more of the patients who were in drug-free remission at 1 year were ACPA negative than were those who were not in remission (62% vs. 50%).

At 16 months, 77 patients (65% of the entire group) were still in drug-free remission. Again, ACPA negativity was more often present among those who were still in drug-free remission than it was in those who were not in remission (80% vs. 58%).

Dr. Wevers-de Boer conducted regression analyses to look for any significant baseline factors that might predict the inability to sustain drug-free remission.

In the univariate analysis, significant factors were a high tender joint count at baseline, being ACPA-positive, and fulfilling the 2010 American College of Rheumatology-European League Against Rheumatism diagnostic criteria. In the multivariate analysis, the combination of high tender joint count and meeting the 2010 diagnostic criteria was significantly associated with an inability to sustain remission.

"Patients who are ACPA positive can achieve drug-free remission almost as often as patients who are ACPA negative, although they are somewhat less often able to sustain that," she said.

Dr. Wevers-de Boer disclosed that she has received grant funding from Abbott, which sponsored the IMPROVED study.

msullivan@frontlinemedcom.com

MADRID – Drug-free remission is possible for rheumatoid arthritis patients with anticitrullinated protein antibodies, although they may not be able to sustain it for as long as ACPA-negative patients.

Still, after treatment with methotrexate and tapered prednisone, more than one-third of ACPA-positive patients experienced drug-free remission for at least some period of time, Dr. Kirsten Wevers-de Boer said at the annual European Congress of Rheumatology.

"With this treatment strategy, the presence of ACPA appears not to preclude drug discontinuation," said Dr. Wevers-de Boer of the department of rheumatology at Leiden University Medical Center in the Netherlands.

She and her colleagues conducted a subanalysis of patients who achieved remission in the IMPROVED study, which examined remission rates in 610 patients with recent-onset rheumatoid or undifferentiated arthritis. They were treated with a two-step regimen of 7 weeks of methotrexate 25 mg/week along with a tapered course of prednisone. Prednisone was started at 60 mg/day and tapered to 7.5 mg/day by the end of the treatment period (Ann. Rheum. Dis. 2013 May 28 [doi:10.1136/annrheumdis-2013-203243]).

Patients not in remission 4 months after the treatment cycle were randomized to either one of two regimens – methotrexate, hydroxychloroquine, sulfasalazine, and low-dose prednisone, or methotrexate plus adalimumab.

Dr. Wevers-de Boer’s subanalysis focused on the 375 patients (61%) who achieved early drug-free remission. They were followed for up to 16 months.

At 1 year, 119 (32%) had remained in drug-free remission. Significantly more of the patients who were in drug-free remission at 1 year were ACPA negative than were those who were not in remission (62% vs. 50%).

At 16 months, 77 patients (65% of the entire group) were still in drug-free remission. Again, ACPA negativity was more often present among those who were still in drug-free remission than it was in those who were not in remission (80% vs. 58%).

Dr. Wevers-de Boer conducted regression analyses to look for any significant baseline factors that might predict the inability to sustain drug-free remission.

In the univariate analysis, significant factors were a high tender joint count at baseline, being ACPA-positive, and fulfilling the 2010 American College of Rheumatology-European League Against Rheumatism diagnostic criteria. In the multivariate analysis, the combination of high tender joint count and meeting the 2010 diagnostic criteria was significantly associated with an inability to sustain remission.

"Patients who are ACPA positive can achieve drug-free remission almost as often as patients who are ACPA negative, although they are somewhat less often able to sustain that," she said.

Dr. Wevers-de Boer disclosed that she has received grant funding from Abbott, which sponsored the IMPROVED study.

msullivan@frontlinemedcom.com

MADRID – Four newly identified serologic biomarkers have the potential to increase the chances of an early diagnosis for patients with rheumatoid arthritis.

When added to the standard biomarker panel, the new markers – UH-RA.1, UH-RA.9, UH-RA.14, and UH-RA.21 – found about 8% more patients with new-onset RA, Dr. Liesbeth De Winter reported at the annual European Congress of Rheumatology.

The current diagnostic methods, based on 2010 RA Classification Criteria and a two-antibody serological panel, miss about one-third of patients with new-onset disease, said Dr. De Winter of the Biomedical Research Institute of Hasselt University, Diepenbeek, Belgium. The resulting delay in diagnosis decreases the chance of a good outcome for the group.

"Early diagnosis is important, because there is a therapeutic window in the first few years during which early intervention and treatment yield a better outcome, and patients are much more likely to go into remission when treated at this time," she said.

Researchers at the same institute first published on these new biomarkers in 2011 (J. Autoimmun. 2011;36:33-46). Since then, Dr. De Winter said, they have been validated and found to be significantly associated with early-onset disease.

The team used the current diagnostic criteria in a group of 292 patients with RA, 97 healthy controls, and 90 rheumatic controls (including patients with arthritis, ankylosing spondylitis, osteoarthritis, and Sjögren’s syndrome). About one-third (34%) of the RA patients were seronegative for the diagnostic biomarkers of rheumatoid factor and anti-citrullinated protein antibodies (ACPAs). This 34% was termed the "serological gap."

But 26% of these patients were also positive for at least one of the four new biomarkers, "narrowing the serological gap by 8%," Dr. De Winter said. Of the 39 patients with very early RA, 13% were also positive for the new biomarkers, she added.

The test should be easy and inexpensive to implement, as it could simply be added to the current biomarker panel in a routine patient workup, she added.

The next step is to examine whether the markers can predict either disease course or therapeutic response, she said. "It’s already been shown that patients who are positive for ACPA respond differently to treatment. We also want to try and identify their role in the disease process, to help us gain some additional knowledge about it."

Identifying more early-stage patients could have a large impact on disease burden, Dr. Maya Buch said during a press briefing on the study.

"There’s currently a risk that some of our early-stage patients are being neglected because the diagnostic criteria as they are now are weighted toward ACPA-positive patients," said Dr. Buch of the University of Leeds, England. "I think it’s likely that even more biomarkers will be identified over time, further increasing our ability to catch these patients early. Incremental work like this fills the need for patients that we are not currently able to diagnose as early as necessary."

Dr. De Winter had no financial disclosures.

msullivan@frontlinemedcom.com

MADRID – Four newly identified serologic biomarkers have the potential to increase the chances of an early diagnosis for patients with rheumatoid arthritis.

When added to the standard biomarker panel, the new markers – UH-RA.1, UH-RA.9, UH-RA.14, and UH-RA.21 – found about 8% more patients with new-onset RA, Dr. Liesbeth De Winter reported at the annual European Congress of Rheumatology.

The current diagnostic methods, based on 2010 RA Classification Criteria and a two-antibody serological panel, miss about one-third of patients with new-onset disease, said Dr. De Winter of the Biomedical Research Institute of Hasselt University, Diepenbeek, Belgium. The resulting delay in diagnosis decreases the chance of a good outcome for the group.

"Early diagnosis is important, because there is a therapeutic window in the first few years during which early intervention and treatment yield a better outcome, and patients are much more likely to go into remission when treated at this time," she said.

Researchers at the same institute first published on these new biomarkers in 2011 (J. Autoimmun. 2011;36:33-46). Since then, Dr. De Winter said, they have been validated and found to be significantly associated with early-onset disease.

The team used the current diagnostic criteria in a group of 292 patients with RA, 97 healthy controls, and 90 rheumatic controls (including patients with arthritis, ankylosing spondylitis, osteoarthritis, and Sjögren’s syndrome). About one-third (34%) of the RA patients were seronegative for the diagnostic biomarkers of rheumatoid factor and anti-citrullinated protein antibodies (ACPAs). This 34% was termed the "serological gap."

But 26% of these patients were also positive for at least one of the four new biomarkers, "narrowing the serological gap by 8%," Dr. De Winter said. Of the 39 patients with very early RA, 13% were also positive for the new biomarkers, she added.

The test should be easy and inexpensive to implement, as it could simply be added to the current biomarker panel in a routine patient workup, she added.

The next step is to examine whether the markers can predict either disease course or therapeutic response, she said. "It’s already been shown that patients who are positive for ACPA respond differently to treatment. We also want to try and identify their role in the disease process, to help us gain some additional knowledge about it."

Identifying more early-stage patients could have a large impact on disease burden, Dr. Maya Buch said during a press briefing on the study.

"There’s currently a risk that some of our early-stage patients are being neglected because the diagnostic criteria as they are now are weighted toward ACPA-positive patients," said Dr. Buch of the University of Leeds, England. "I think it’s likely that even more biomarkers will be identified over time, further increasing our ability to catch these patients early. Incremental work like this fills the need for patients that we are not currently able to diagnose as early as necessary."

Dr. De Winter had no financial disclosures.

msullivan@frontlinemedcom.com

MADRID – Four newly identified serologic biomarkers have the potential to increase the chances of an early diagnosis for patients with rheumatoid arthritis.

When added to the standard biomarker panel, the new markers – UH-RA.1, UH-RA.9, UH-RA.14, and UH-RA.21 – found about 8% more patients with new-onset RA, Dr. Liesbeth De Winter reported at the annual European Congress of Rheumatology.

The current diagnostic methods, based on 2010 RA Classification Criteria and a two-antibody serological panel, miss about one-third of patients with new-onset disease, said Dr. De Winter of the Biomedical Research Institute of Hasselt University, Diepenbeek, Belgium. The resulting delay in diagnosis decreases the chance of a good outcome for the group.

"Early diagnosis is important, because there is a therapeutic window in the first few years during which early intervention and treatment yield a better outcome, and patients are much more likely to go into remission when treated at this time," she said.

Researchers at the same institute first published on these new biomarkers in 2011 (J. Autoimmun. 2011;36:33-46). Since then, Dr. De Winter said, they have been validated and found to be significantly associated with early-onset disease.

The team used the current diagnostic criteria in a group of 292 patients with RA, 97 healthy controls, and 90 rheumatic controls (including patients with arthritis, ankylosing spondylitis, osteoarthritis, and Sjögren’s syndrome). About one-third (34%) of the RA patients were seronegative for the diagnostic biomarkers of rheumatoid factor and anti-citrullinated protein antibodies (ACPAs). This 34% was termed the "serological gap."

But 26% of these patients were also positive for at least one of the four new biomarkers, "narrowing the serological gap by 8%," Dr. De Winter said. Of the 39 patients with very early RA, 13% were also positive for the new biomarkers, she added.

The test should be easy and inexpensive to implement, as it could simply be added to the current biomarker panel in a routine patient workup, she added.

The next step is to examine whether the markers can predict either disease course or therapeutic response, she said. "It’s already been shown that patients who are positive for ACPA respond differently to treatment. We also want to try and identify their role in the disease process, to help us gain some additional knowledge about it."

Identifying more early-stage patients could have a large impact on disease burden, Dr. Maya Buch said during a press briefing on the study.

"There’s currently a risk that some of our early-stage patients are being neglected because the diagnostic criteria as they are now are weighted toward ACPA-positive patients," said Dr. Buch of the University of Leeds, England. "I think it’s likely that even more biomarkers will be identified over time, further increasing our ability to catch these patients early. Incremental work like this fills the need for patients that we are not currently able to diagnose as early as necessary."

Dr. De Winter had no financial disclosures.

msullivan@frontlinemedcom.com

Two biosimilar versions of infliximab have been recommended for approval in Europe, putting them on track to become the first monoclonal antibody biosimilars to be approved by the European Medicines Agency.*

On June 28, the agency's Committee for Medicinal Products for Human Use (CHMP) announced that it had recommended marketing authorizations for Remsima and Inflectra. Both contain the monoclonal antibody infliximab and were shown to be similar to Remicade, approved in the European Union since 1999. Authorization, or approval, of the two biosimilars is for the same indications as Remicade, which include rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis.

This marks "the first time that the biosimilar concept has been successfully applied to such a complex molecule," an EMA statement said.

Infliximab, a tumor necrosis factor (TNF) blocker, was approved in 1998 in the United States and is also marketed as Remicade, for similar indications.

In Europe, the first biosimilar medication was approved in 2006, and a total of 12 biosimilar medications have been approved using a regulatory framework designed specifically for approval of biosimilars. A product-specific guideline for monoclonal antibodies has been established since December 2012. For approval, studies are required to show that the medication "does not have any meaningful differences from the reference medicine in terms of its quality, safety, and efficacy," according to the statement. The applicant must also establish a risk management plan that confirms the long-term safety and efficacy of the product, and monitors unexpected rare adverse events associated with the clinical use of the product.

The United States lags behind Europe with regard to the approval of biosimilars. A specific approval pathway for such products was created in the Affordable Care Act in March 2010. In 2012, the Food and Drug Administration issued draft guidance aimed at helping the developers of biosimilar products understand the expectations for such products and to provide a clear regulatory pathway for approval.

But to date, no biosimilar product has been approved in the United States.

emechcatie@frontlinemedcom.com

*CORRECTION, 7/9/2013: An earlier version of this story incorrectly described the marketing status of the two biosimilars.

Two biosimilar versions of infliximab have been recommended for approval in Europe, putting them on track to become the first monoclonal antibody biosimilars to be approved by the European Medicines Agency.*

On June 28, the agency's Committee for Medicinal Products for Human Use (CHMP) announced that it had recommended marketing authorizations for Remsima and Inflectra. Both contain the monoclonal antibody infliximab and were shown to be similar to Remicade, approved in the European Union since 1999. Authorization, or approval, of the two biosimilars is for the same indications as Remicade, which include rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis.

This marks "the first time that the biosimilar concept has been successfully applied to such a complex molecule," an EMA statement said.

Infliximab, a tumor necrosis factor (TNF) blocker, was approved in 1998 in the United States and is also marketed as Remicade, for similar indications.

In Europe, the first biosimilar medication was approved in 2006, and a total of 12 biosimilar medications have been approved using a regulatory framework designed specifically for approval of biosimilars. A product-specific guideline for monoclonal antibodies has been established since December 2012. For approval, studies are required to show that the medication "does not have any meaningful differences from the reference medicine in terms of its quality, safety, and efficacy," according to the statement. The applicant must also establish a risk management plan that confirms the long-term safety and efficacy of the product, and monitors unexpected rare adverse events associated with the clinical use of the product.

The United States lags behind Europe with regard to the approval of biosimilars. A specific approval pathway for such products was created in the Affordable Care Act in March 2010. In 2012, the Food and Drug Administration issued draft guidance aimed at helping the developers of biosimilar products understand the expectations for such products and to provide a clear regulatory pathway for approval.

But to date, no biosimilar product has been approved in the United States.

emechcatie@frontlinemedcom.com

*CORRECTION, 7/9/2013: An earlier version of this story incorrectly described the marketing status of the two biosimilars.

Two biosimilar versions of infliximab have been recommended for approval in Europe, putting them on track to become the first monoclonal antibody biosimilars to be approved by the European Medicines Agency.*

On June 28, the agency's Committee for Medicinal Products for Human Use (CHMP) announced that it had recommended marketing authorizations for Remsima and Inflectra. Both contain the monoclonal antibody infliximab and were shown to be similar to Remicade, approved in the European Union since 1999. Authorization, or approval, of the two biosimilars is for the same indications as Remicade, which include rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis.

This marks "the first time that the biosimilar concept has been successfully applied to such a complex molecule," an EMA statement said.

Infliximab, a tumor necrosis factor (TNF) blocker, was approved in 1998 in the United States and is also marketed as Remicade, for similar indications.

In Europe, the first biosimilar medication was approved in 2006, and a total of 12 biosimilar medications have been approved using a regulatory framework designed specifically for approval of biosimilars. A product-specific guideline for monoclonal antibodies has been established since December 2012. For approval, studies are required to show that the medication "does not have any meaningful differences from the reference medicine in terms of its quality, safety, and efficacy," according to the statement. The applicant must also establish a risk management plan that confirms the long-term safety and efficacy of the product, and monitors unexpected rare adverse events associated with the clinical use of the product.

The United States lags behind Europe with regard to the approval of biosimilars. A specific approval pathway for such products was created in the Affordable Care Act in March 2010. In 2012, the Food and Drug Administration issued draft guidance aimed at helping the developers of biosimilar products understand the expectations for such products and to provide a clear regulatory pathway for approval.

But to date, no biosimilar product has been approved in the United States.

emechcatie@frontlinemedcom.com

*CORRECTION, 7/9/2013: An earlier version of this story incorrectly described the marketing status of the two biosimilars.

MADRID – Patients with early, active rheumatoid arthritis who took tocilizumab – either alone or in combination with methotrexate – continued to benefit from it by the end of a 2-year study.

About half of those on either treatment strategy in the study achieved remission by the end of the first year and this did not change appreciably by the end of the second year. There was also a very low rate of radiographic progression, Dr. Tom Huizinga said at the annual European Congress of Rheumatology.

The results confirm and extend the earlier findings of ACT-RAY, a 2-year, randomized, placebo-controlled study of tocilizumab employed as a switch or add-on therapy for patients with early, active rheumatoid arthritis (RA). The 24-week data, published earlier this year, showed that tocilizumab was just as effective without methotrexate as with it, suggesting that it could be employed as monotherapy (Ann. Rheum. Dis. 2013;72:43-50).

Michele Sullivan/IMNG Medical Media

All 553 patients in ACT-RAY received open-label tocilizumab 8 mg/kg intravenously every 4 weeks. They were randomized to the switch strategy (tocilizumab 8 mg/kg IV every 4 weeks with oral placebo) or the add-on strategy (tocilizumab 8 mg/kg IV every 4 weeks plus 2.5 mg methotrexate), said Dr. Huizinga, head of the department of rheumatology at Leiden (The Netherlands) University Medical Center.

Most of the patients (81%) were women; mean age was 53 years. Patients had a mean disease duration of 8 years and a mean Disease Activity Score–28 (DAS28) of 6.4.

Most of the study group (433) completed the second year of treatment. Reasons for withdrawal included lack of efficacy (2% in the add-on strategy group and 5% in the switch strategy group) and adverse events (10% of add-on patients and 11% of switch). There were three deaths in the add-on group and six in the switch group.

Sustained remission was defined as a DAS28 of less than 2.6 at two consecutive visits separated by 12 weeks. By week 52, about 50% of the overall cohort (53% add-on strategy and 47% switch strategy) had achieved remission and were able to discontinue tocilizumab.

By week 104, 86% of the overall cohort had experienced a flare in disease activity, with a median time of 90 days from tocilizumab discontinuation. Most of those patients restarted tocilizumab. The medication continued to be effective. The mean DAS28 at flare was 4.46, dropping to a mean of 2.99 within 4 weeks of restarting treatment.

The mean DAS28 score at week 104 was unchanged from the score at week 52, decreasing by 3.6 from baseline in both groups. The large majority of each group experienced no radiographic progression during year 2 (94% of the add-on and 91% of the switch groups).

By the end of the study at week 104, 23% of the add-on group and 18% of the switch group were in remission as measured by the Clinical Disease Activity Index – virtually identical to CDAI remission rates at week 52.

The safety results were consistent with previous findings, Dr. Huizinga said. Serious adverse events and infections occurred in 15% of the add-on group and 4% of the switch group.

Liver enzyme elevations were more common among those in the add-on group. Elevations of up to three times the upper limit of normal of alanine aminotransferase occurred in 58% of the add-on group and 40% of the switch group. Elevations of up to five times the upper limit occurred in 13% of the add-on group and 5% of the switch group. Aspartate transaminase elevations of up to three times the upper limit of normal occurred in 51% of the add-on group and 30% of the switch group. Elevations of up to five times the upper limit of normal occurred in 5% of the add-on and 2% of the switch groups.

During a discussion period after his presentation, Dr. Huizinga addressed the issue of clinical impact, saying all of the information isn’t in yet. Patients will be followed for an additional year for structural or joint damage.

"Clinical meaningfulness is an intense discussion that we will have to conduct," he said. "I’m not quite sure of it myself yet."

The study was funded by F. Hoffmann-La Roche Ltd. Dr. Huizinga disclosed that he is a consultant for Abbott, Axis Shield Diagnostics, Biotest AG, Bristol-Myers Squibb, Crescendo Bioscience, Roche, Novartis, Schering-Plough, UCB, Wyeth, and Pfizer.

msullivan@frontlinemedcom.com

MADRID – Patients with early, active rheumatoid arthritis who took tocilizumab – either alone or in combination with methotrexate – continued to benefit from it by the end of a 2-year study.

About half of those on either treatment strategy in the study achieved remission by the end of the first year and this did not change appreciably by the end of the second year. There was also a very low rate of radiographic progression, Dr. Tom Huizinga said at the annual European Congress of Rheumatology.

The results confirm and extend the earlier findings of ACT-RAY, a 2-year, randomized, placebo-controlled study of tocilizumab employed as a switch or add-on therapy for patients with early, active rheumatoid arthritis (RA). The 24-week data, published earlier this year, showed that tocilizumab was just as effective without methotrexate as with it, suggesting that it could be employed as monotherapy (Ann. Rheum. Dis. 2013;72:43-50).

Michele Sullivan/IMNG Medical Media

All 553 patients in ACT-RAY received open-label tocilizumab 8 mg/kg intravenously every 4 weeks. They were randomized to the switch strategy (tocilizumab 8 mg/kg IV every 4 weeks with oral placebo) or the add-on strategy (tocilizumab 8 mg/kg IV every 4 weeks plus 2.5 mg methotrexate), said Dr. Huizinga, head of the department of rheumatology at Leiden (The Netherlands) University Medical Center.

Most of the patients (81%) were women; mean age was 53 years. Patients had a mean disease duration of 8 years and a mean Disease Activity Score–28 (DAS28) of 6.4.

Most of the study group (433) completed the second year of treatment. Reasons for withdrawal included lack of efficacy (2% in the add-on strategy group and 5% in the switch strategy group) and adverse events (10% of add-on patients and 11% of switch). There were three deaths in the add-on group and six in the switch group.

Sustained remission was defined as a DAS28 of less than 2.6 at two consecutive visits separated by 12 weeks. By week 52, about 50% of the overall cohort (53% add-on strategy and 47% switch strategy) had achieved remission and were able to discontinue tocilizumab.

By week 104, 86% of the overall cohort had experienced a flare in disease activity, with a median time of 90 days from tocilizumab discontinuation. Most of those patients restarted tocilizumab. The medication continued to be effective. The mean DAS28 at flare was 4.46, dropping to a mean of 2.99 within 4 weeks of restarting treatment.

The mean DAS28 score at week 104 was unchanged from the score at week 52, decreasing by 3.6 from baseline in both groups. The large majority of each group experienced no radiographic progression during year 2 (94% of the add-on and 91% of the switch groups).

By the end of the study at week 104, 23% of the add-on group and 18% of the switch group were in remission as measured by the Clinical Disease Activity Index – virtually identical to CDAI remission rates at week 52.

The safety results were consistent with previous findings, Dr. Huizinga said. Serious adverse events and infections occurred in 15% of the add-on group and 4% of the switch group.

Liver enzyme elevations were more common among those in the add-on group. Elevations of up to three times the upper limit of normal of alanine aminotransferase occurred in 58% of the add-on group and 40% of the switch group. Elevations of up to five times the upper limit occurred in 13% of the add-on group and 5% of the switch group. Aspartate transaminase elevations of up to three times the upper limit of normal occurred in 51% of the add-on group and 30% of the switch group. Elevations of up to five times the upper limit of normal occurred in 5% of the add-on and 2% of the switch groups.

During a discussion period after his presentation, Dr. Huizinga addressed the issue of clinical impact, saying all of the information isn’t in yet. Patients will be followed for an additional year for structural or joint damage.

"Clinical meaningfulness is an intense discussion that we will have to conduct," he said. "I’m not quite sure of it myself yet."

The study was funded by F. Hoffmann-La Roche Ltd. Dr. Huizinga disclosed that he is a consultant for Abbott, Axis Shield Diagnostics, Biotest AG, Bristol-Myers Squibb, Crescendo Bioscience, Roche, Novartis, Schering-Plough, UCB, Wyeth, and Pfizer.

msullivan@frontlinemedcom.com

MADRID – Patients with early, active rheumatoid arthritis who took tocilizumab – either alone or in combination with methotrexate – continued to benefit from it by the end of a 2-year study.

About half of those on either treatment strategy in the study achieved remission by the end of the first year and this did not change appreciably by the end of the second year. There was also a very low rate of radiographic progression, Dr. Tom Huizinga said at the annual European Congress of Rheumatology.

The results confirm and extend the earlier findings of ACT-RAY, a 2-year, randomized, placebo-controlled study of tocilizumab employed as a switch or add-on therapy for patients with early, active rheumatoid arthritis (RA). The 24-week data, published earlier this year, showed that tocilizumab was just as effective without methotrexate as with it, suggesting that it could be employed as monotherapy (Ann. Rheum. Dis. 2013;72:43-50).

Michele Sullivan/IMNG Medical Media

All 553 patients in ACT-RAY received open-label tocilizumab 8 mg/kg intravenously every 4 weeks. They were randomized to the switch strategy (tocilizumab 8 mg/kg IV every 4 weeks with oral placebo) or the add-on strategy (tocilizumab 8 mg/kg IV every 4 weeks plus 2.5 mg methotrexate), said Dr. Huizinga, head of the department of rheumatology at Leiden (The Netherlands) University Medical Center.

Most of the patients (81%) were women; mean age was 53 years. Patients had a mean disease duration of 8 years and a mean Disease Activity Score–28 (DAS28) of 6.4.

Most of the study group (433) completed the second year of treatment. Reasons for withdrawal included lack of efficacy (2% in the add-on strategy group and 5% in the switch strategy group) and adverse events (10% of add-on patients and 11% of switch). There were three deaths in the add-on group and six in the switch group.

Sustained remission was defined as a DAS28 of less than 2.6 at two consecutive visits separated by 12 weeks. By week 52, about 50% of the overall cohort (53% add-on strategy and 47% switch strategy) had achieved remission and were able to discontinue tocilizumab.

By week 104, 86% of the overall cohort had experienced a flare in disease activity, with a median time of 90 days from tocilizumab discontinuation. Most of those patients restarted tocilizumab. The medication continued to be effective. The mean DAS28 at flare was 4.46, dropping to a mean of 2.99 within 4 weeks of restarting treatment.

The mean DAS28 score at week 104 was unchanged from the score at week 52, decreasing by 3.6 from baseline in both groups. The large majority of each group experienced no radiographic progression during year 2 (94% of the add-on and 91% of the switch groups).

By the end of the study at week 104, 23% of the add-on group and 18% of the switch group were in remission as measured by the Clinical Disease Activity Index – virtually identical to CDAI remission rates at week 52.

The safety results were consistent with previous findings, Dr. Huizinga said. Serious adverse events and infections occurred in 15% of the add-on group and 4% of the switch group.

Liver enzyme elevations were more common among those in the add-on group. Elevations of up to three times the upper limit of normal of alanine aminotransferase occurred in 58% of the add-on group and 40% of the switch group. Elevations of up to five times the upper limit occurred in 13% of the add-on group and 5% of the switch group. Aspartate transaminase elevations of up to three times the upper limit of normal occurred in 51% of the add-on group and 30% of the switch group. Elevations of up to five times the upper limit of normal occurred in 5% of the add-on and 2% of the switch groups.

During a discussion period after his presentation, Dr. Huizinga addressed the issue of clinical impact, saying all of the information isn’t in yet. Patients will be followed for an additional year for structural or joint damage.

"Clinical meaningfulness is an intense discussion that we will have to conduct," he said. "I’m not quite sure of it myself yet."

The study was funded by F. Hoffmann-La Roche Ltd. Dr. Huizinga disclosed that he is a consultant for Abbott, Axis Shield Diagnostics, Biotest AG, Bristol-Myers Squibb, Crescendo Bioscience, Roche, Novartis, Schering-Plough, UCB, Wyeth, and Pfizer.

msullivan@frontlinemedcom.com

MADRID – Being overweight or obese makes it much more difficult for patients with early rheumatoid arthritis to achieve remission and significantly increases the chance that they will need a biologic by the end of the first treatment year.

The finding speaks to the role that weight can play in RA management, Dr. Elisa Gremese said during the annual European Congress of Rheumatology.

"Obesity is considered a systemic low-grade inflammatory state, and adipose tissue is a proinflammatory cytokine-producing factory," Dr. Gremese said during a press briefing. "Studies continue to show that obesity may be contributing to the rise in RA and is associated with a worse course of disease and more disability."

She examined the relationship between weight and first-year therapeutic outcomes among 346 patients with early rheumatoid arthritis; 33% of these had very early disease of less than 6 months’ duration. Normal weight was considered to be a body mass index of less than 25 kg/m²; overweight was a BMI of 25-30 kg/m², and obesity was a BMI of greater than 30 kg/m². About half of the patients (47%) were normal weight, 39% were overweight, and the remainder were obese, said Dr. Gremese of the Università Cattolica del Sacro Cuore in Rome.

All patients received up to 25 mg methotrexate each week, with or without steroids. In cases in which a patient didn’t achieve at least a "good" response (a change of at least 1.2 on the Disease Activity Score [DAS] 28), a tumor necrosis factor (TNF) blocker was added to the treatment regimen.

Overweight and obese patients had a significantly lower rate of remission as measured by both the DAS and the Clinical Disease Activity Index (CDAI) Score.

At 12 months, 49% of the normal weight group, 29% of the overweight group, and 34% of the obese group reached remission as measured by the DAS. Remission according to the CDAI criteria occurred in 50% of the normal weight group, 37% of the overweight group, and 31% of the obese group.

By the end of the first year, significantly more overweight and obese patients were taking an anti-TNF medication than were normal weight patients (29% and 28%, compared with 16%, respectively).

A multivariate analysis found that having a body mass index of at least 25 kg/m² at baseline more than doubled the risk of DAS nonremission (odds ratio, 2.4) at 12 months, and nearly doubled the risk of CDAI nonremission (OR, 1.8).

"In the general population, the prevalence of overweight and obesity now reaches 50%," Dr. Gremese said. "We should look at this as a modifiable risk factor" that can be changed to help patients reach a better outcome.

She added that her group has started a dedicated outpatient center with a multidisciplinary program to help patients with RA and other rheumatic diseases with weight loss. "They work with a dietitian and psychologist as well as rheumatologist," she said.

Dr. Gremese had no financial declarations.

msullivan@frontlinemedcom.com

MADRID – Being overweight or obese makes it much more difficult for patients with early rheumatoid arthritis to achieve remission and significantly increases the chance that they will need a biologic by the end of the first treatment year.

The finding speaks to the role that weight can play in RA management, Dr. Elisa Gremese said during the annual European Congress of Rheumatology.

"Obesity is considered a systemic low-grade inflammatory state, and adipose tissue is a proinflammatory cytokine-producing factory," Dr. Gremese said during a press briefing. "Studies continue to show that obesity may be contributing to the rise in RA and is associated with a worse course of disease and more disability."

She examined the relationship between weight and first-year therapeutic outcomes among 346 patients with early rheumatoid arthritis; 33% of these had very early disease of less than 6 months’ duration. Normal weight was considered to be a body mass index of less than 25 kg/m²; overweight was a BMI of 25-30 kg/m², and obesity was a BMI of greater than 30 kg/m². About half of the patients (47%) were normal weight, 39% were overweight, and the remainder were obese, said Dr. Gremese of the Università Cattolica del Sacro Cuore in Rome.

All patients received up to 25 mg methotrexate each week, with or without steroids. In cases in which a patient didn’t achieve at least a "good" response (a change of at least 1.2 on the Disease Activity Score [DAS] 28), a tumor necrosis factor (TNF) blocker was added to the treatment regimen.

Overweight and obese patients had a significantly lower rate of remission as measured by both the DAS and the Clinical Disease Activity Index (CDAI) Score.

At 12 months, 49% of the normal weight group, 29% of the overweight group, and 34% of the obese group reached remission as measured by the DAS. Remission according to the CDAI criteria occurred in 50% of the normal weight group, 37% of the overweight group, and 31% of the obese group.

By the end of the first year, significantly more overweight and obese patients were taking an anti-TNF medication than were normal weight patients (29% and 28%, compared with 16%, respectively).

A multivariate analysis found that having a body mass index of at least 25 kg/m² at baseline more than doubled the risk of DAS nonremission (odds ratio, 2.4) at 12 months, and nearly doubled the risk of CDAI nonremission (OR, 1.8).

"In the general population, the prevalence of overweight and obesity now reaches 50%," Dr. Gremese said. "We should look at this as a modifiable risk factor" that can be changed to help patients reach a better outcome.

She added that her group has started a dedicated outpatient center with a multidisciplinary program to help patients with RA and other rheumatic diseases with weight loss. "They work with a dietitian and psychologist as well as rheumatologist," she said.

Dr. Gremese had no financial declarations.

msullivan@frontlinemedcom.com

MADRID – Being overweight or obese makes it much more difficult for patients with early rheumatoid arthritis to achieve remission and significantly increases the chance that they will need a biologic by the end of the first treatment year.

The finding speaks to the role that weight can play in RA management, Dr. Elisa Gremese said during the annual European Congress of Rheumatology.

"Obesity is considered a systemic low-grade inflammatory state, and adipose tissue is a proinflammatory cytokine-producing factory," Dr. Gremese said during a press briefing. "Studies continue to show that obesity may be contributing to the rise in RA and is associated with a worse course of disease and more disability."

She examined the relationship between weight and first-year therapeutic outcomes among 346 patients with early rheumatoid arthritis; 33% of these had very early disease of less than 6 months’ duration. Normal weight was considered to be a body mass index of less than 25 kg/m²; overweight was a BMI of 25-30 kg/m², and obesity was a BMI of greater than 30 kg/m². About half of the patients (47%) were normal weight, 39% were overweight, and the remainder were obese, said Dr. Gremese of the Università Cattolica del Sacro Cuore in Rome.

All patients received up to 25 mg methotrexate each week, with or without steroids. In cases in which a patient didn’t achieve at least a "good" response (a change of at least 1.2 on the Disease Activity Score [DAS] 28), a tumor necrosis factor (TNF) blocker was added to the treatment regimen.

Overweight and obese patients had a significantly lower rate of remission as measured by both the DAS and the Clinical Disease Activity Index (CDAI) Score.

At 12 months, 49% of the normal weight group, 29% of the overweight group, and 34% of the obese group reached remission as measured by the DAS. Remission according to the CDAI criteria occurred in 50% of the normal weight group, 37% of the overweight group, and 31% of the obese group.

By the end of the first year, significantly more overweight and obese patients were taking an anti-TNF medication than were normal weight patients (29% and 28%, compared with 16%, respectively).

A multivariate analysis found that having a body mass index of at least 25 kg/m² at baseline more than doubled the risk of DAS nonremission (odds ratio, 2.4) at 12 months, and nearly doubled the risk of CDAI nonremission (OR, 1.8).

"In the general population, the prevalence of overweight and obesity now reaches 50%," Dr. Gremese said. "We should look at this as a modifiable risk factor" that can be changed to help patients reach a better outcome.

She added that her group has started a dedicated outpatient center with a multidisciplinary program to help patients with RA and other rheumatic diseases with weight loss. "They work with a dietitian and psychologist as well as rheumatologist," she said.

Dr. Gremese had no financial declarations.

msullivan@frontlinemedcom.com

MADRID – When rheumatoid arthritis patients fail initial treatment with methotrexate monotherapy, are they better served by a less expensive step-up treatment or the one that may better slow their radiographic progression and produce faster responses?

That seems to be the choice between step-up from methotrexate monotherapy by adding synthetic disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine and hydroxychloroquine, or by adding a tumor necrosis factor (TNF) inhibitor such as etanercept.

Mitchel L. Zoler/IMNG Medical Media

The RACAT (Rheumatoid Arthritis: Comparison of Active Therapies) trial tested those two options in 353 rheumatoid arthritis (RA) patients at 36 U.S. or Canadian sites between July 2007 and December 2010. The study’s primary endpoint, improvement in average disease activity score in 28 joints (DAS28) from baseline to 48 weeks of treatment, was similar in both treatment arms, proving the noninferiority of the triple synthetic DMARD regimen against the etanercept, biological arm, Dr. James R. O’Dell reported in a poster at the annual European Congress of Rheumatology. The results also appeared online simultaneously with Dr. O’Dell’s poster presentation (N. Engl. J. Med. 2013 June 11 [doi: 10.1056/NEJMoal1303006]).

"We showed that starting first with a TNF inhibitor or first with triple therapy resulted in the same outcomes. But costs were not the same. We [successfully] treated another 30% of patients who did not need a biologic" with the synthetic triple therapy. "And in the patients where triple therapy doesn’t work, you can change them to a biologic and they have identical outcomes, clinically by DAS28 and radiographically," compared with patients who began on etanercept added to methotrexate from the start, he said. Dr. O’Dell is chief of rheumatology at the VA Medical Center in Omaha, Neb., and professor of medicine at the University of Nebraska.

"Nothing is lost for the patient; if they don’t do well on triple therapy they can switch to a biological. The data are persuasive and the economic case is easy to make. You absolutely ought to go with triple therapy," he concluded based on the study findings.

But "it is very difficult to get physicians to buy into this" strategy, he said in an interview. TNF inhibitors such as etanercept and other biological DMARDs are "seductive," Dr. O’Dell said, because they are effective, work quickly, and appear more "targeted" than synthetic DMARDs, and they are promoted by well-financed marketing campaigns.

Dr. O’Dell conceded that the study data showed a signal of more radiographic progression with triple synthetic DMARD treatment that could potentially, over time, accrue to more substantial differences. At 48 weeks after the onset of treatment, patients on triple therapy had an average 0.54-point increase (worsening) in their van der Heijde modified Sharp score, compared with an average 0.29-point rise in the patients who received etanercept, a 0.25-point average difference in favor of etanercept that did not reach statistical significance.

But this trend toward greater radiographic progression in patients on triple therapy was consistent with the statistically significant, roughly 1-point average additional increased radiographic progression with triple therapy, compared with patients on methotrexate plus etanercept, that was seen after 2 years of follow-up in the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial (Arthritis Rheum. 2012;64:2824-35).

The TEAR study, which enrolled patients with very early RA, included a subgroup with an inadequate response to methotrexate monotherapy, and in that subgroup, patients randomized to triple therapy and those randomized to etanercept plus methotrexate had similar clinical outcomes, consistent with the new study findings.

"It’s hard to say that 1 or 2 units on the Sharp score doesn’t matter much, even if you don’t see the difference for several years," commented Dr. Daniel Furst, professor of medicine and director of the Rheumatology Clinical Research Center at the University of California, Los Angeles.

"Triple therapy is effective clinically, but it doesn’t do so well for x-rays. There are relationships between a 1 or 2 Sharp score difference and long-term outcomes. Across the board with biologics, the difference is 1 or 2 Sharp units. If one’s philosophy is to hit the RA hard and stop it, then perhaps a biologic is better," Dr. Furst commented in an interview.

But another view was that triple therapy could play a useful and cost-effective role. The new findings, along with the TEAR results, make "initial treatment of early RA with triple therapy a reasonable approach," said Dr. Joel M. Kremer, a professor of medicine at Albany (N.Y.) Medical College and director of research at the Center for Rheumatology in Albany. The only clear downside is that if triple therapy doesn’t work, the patient loses time, but that’s true for every treatment option, he noted.

"We don’t usually have the opportunity to hear the data for generic drugs" as much as for brand-name formulations, Dr. Kremer said in an interview. "Will data like this substantially change prescribing patterns? Probably not, but what might happen is that insurers may look at these data and say that patients should fail triple therapy before starting a biologic. That would be a sea change" for rheumatology, he added.

"I have always used methotrexate first, usually in combination with hydroxychloroquine," Dr. Kremer said. He has not usually also prescribed sulfasalazine, but said he would consider adding it based on the new data.

The new study enrolled patients with a DAS28 score of 4.4 or higher despite at least 12 weeks of stable methotrexate therapy with a weekly dosage of 15-25 mg. The patients averaged about 57 years old. After the first 24 weeks on randomized treatment, patients who did not have a decrease in their DAS28 of at least 1.2 units switched to the alternate regimens. The primary outcome was change in DAS28 at week 48 according to initial treatment assignment; the researchers collected 48-week DAS28 scores from 309 enrolled patients. The mean change in DAS28 from baseline at 48 weeks was a 2.12-unit reduction in the triple-therapy patients and a 2.29-unit reduction in the etanercept patients, an average 0.17-unit difference between the two treatment arms that was not statistically significant and that fell within the study’s prespecified range for noninferiority for triple therapy.

A similar percentage of patients, 27%, in each of the treatment arms switched to the alternate therapy at 24 weeks due to lack of an adequate initial response. There were also no statistically significant differences between the treatment arms in their rate of American College of Rheumatology (ACR) 20 and 50 responses at both 24 and 48 weeks.

The results showed significant differences between the treatment arms after the first 24 weeks of treatment for higher-level responses. For example, the percentage of patients achieving an ACR 70 response was 5% in the triple-therapy patients and 16% in the etanercept patients, a statistically significant difference. The rate of patients with a DAS28 score of 2.6 points or less at 24 weeks was 13% in the triple-therapy patients and 22% in those on etanercept, a significant difference.

Based on findings like these, "I would start a biologic in a patient who failed high-dose methotrexate and had poor prognostic factors and highly active disease, because at 6 months etanercept had the edge," said Dr. Edward C. Keystone, director of the Centre for Arthritis and Autoimmune Disease at Mount Sinai Hospital in Toronto, and a coinvestigator on the new study. But for all the other patients, "why not start on triple therapy first if you can switch them later if needed and the patients do well?" he asked. "The important observation is that the same percentage of patients failed in each arm. That is a huge message."

The RACAT study received no commercial support. Dr. O’Dell said that he had no disclosures. Dr. Furst has been a consultant to or received grant support from Abbott, Amgen, Bristol-Myers Squibb, and other companies. Dr. Kremer has been a consultant to or received grant support from Pfizer, Abbott, Genentech, and other companies. Dr. Keystone said that he has been a consultant to or has received research grants from Amgen, Pfizer, Merck, and other companies.

mzoler@frontlinemedcom.com On Twitter @mitchelzoler

MADRID – When rheumatoid arthritis patients fail initial treatment with methotrexate monotherapy, are they better served by a less expensive step-up treatment or the one that may better slow their radiographic progression and produce faster responses?

That seems to be the choice between step-up from methotrexate monotherapy by adding synthetic disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine and hydroxychloroquine, or by adding a tumor necrosis factor (TNF) inhibitor such as etanercept.

Mitchel L. Zoler/IMNG Medical Media

The RACAT (Rheumatoid Arthritis: Comparison of Active Therapies) trial tested those two options in 353 rheumatoid arthritis (RA) patients at 36 U.S. or Canadian sites between July 2007 and December 2010. The study’s primary endpoint, improvement in average disease activity score in 28 joints (DAS28) from baseline to 48 weeks of treatment, was similar in both treatment arms, proving the noninferiority of the triple synthetic DMARD regimen against the etanercept, biological arm, Dr. James R. O’Dell reported in a poster at the annual European Congress of Rheumatology. The results also appeared online simultaneously with Dr. O’Dell’s poster presentation (N. Engl. J. Med. 2013 June 11 [doi: 10.1056/NEJMoal1303006]).

"We showed that starting first with a TNF inhibitor or first with triple therapy resulted in the same outcomes. But costs were not the same. We [successfully] treated another 30% of patients who did not need a biologic" with the synthetic triple therapy. "And in the patients where triple therapy doesn’t work, you can change them to a biologic and they have identical outcomes, clinically by DAS28 and radiographically," compared with patients who began on etanercept added to methotrexate from the start, he said. Dr. O’Dell is chief of rheumatology at the VA Medical Center in Omaha, Neb., and professor of medicine at the University of Nebraska.

"Nothing is lost for the patient; if they don’t do well on triple therapy they can switch to a biological. The data are persuasive and the economic case is easy to make. You absolutely ought to go with triple therapy," he concluded based on the study findings.

But "it is very difficult to get physicians to buy into this" strategy, he said in an interview. TNF inhibitors such as etanercept and other biological DMARDs are "seductive," Dr. O’Dell said, because they are effective, work quickly, and appear more "targeted" than synthetic DMARDs, and they are promoted by well-financed marketing campaigns.

Dr. O’Dell conceded that the study data showed a signal of more radiographic progression with triple synthetic DMARD treatment that could potentially, over time, accrue to more substantial differences. At 48 weeks after the onset of treatment, patients on triple therapy had an average 0.54-point increase (worsening) in their van der Heijde modified Sharp score, compared with an average 0.29-point rise in the patients who received etanercept, a 0.25-point average difference in favor of etanercept that did not reach statistical significance.

But this trend toward greater radiographic progression in patients on triple therapy was consistent with the statistically significant, roughly 1-point average additional increased radiographic progression with triple therapy, compared with patients on methotrexate plus etanercept, that was seen after 2 years of follow-up in the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial (Arthritis Rheum. 2012;64:2824-35).

The TEAR study, which enrolled patients with very early RA, included a subgroup with an inadequate response to methotrexate monotherapy, and in that subgroup, patients randomized to triple therapy and those randomized to etanercept plus methotrexate had similar clinical outcomes, consistent with the new study findings.

"It’s hard to say that 1 or 2 units on the Sharp score doesn’t matter much, even if you don’t see the difference for several years," commented Dr. Daniel Furst, professor of medicine and director of the Rheumatology Clinical Research Center at the University of California, Los Angeles.

"Triple therapy is effective clinically, but it doesn’t do so well for x-rays. There are relationships between a 1 or 2 Sharp score difference and long-term outcomes. Across the board with biologics, the difference is 1 or 2 Sharp units. If one’s philosophy is to hit the RA hard and stop it, then perhaps a biologic is better," Dr. Furst commented in an interview.

But another view was that triple therapy could play a useful and cost-effective role. The new findings, along with the TEAR results, make "initial treatment of early RA with triple therapy a reasonable approach," said Dr. Joel M. Kremer, a professor of medicine at Albany (N.Y.) Medical College and director of research at the Center for Rheumatology in Albany. The only clear downside is that if triple therapy doesn’t work, the patient loses time, but that’s true for every treatment option, he noted.

"We don’t usually have the opportunity to hear the data for generic drugs" as much as for brand-name formulations, Dr. Kremer said in an interview. "Will data like this substantially change prescribing patterns? Probably not, but what might happen is that insurers may look at these data and say that patients should fail triple therapy before starting a biologic. That would be a sea change" for rheumatology, he added.

"I have always used methotrexate first, usually in combination with hydroxychloroquine," Dr. Kremer said. He has not usually also prescribed sulfasalazine, but said he would consider adding it based on the new data.

The new study enrolled patients with a DAS28 score of 4.4 or higher despite at least 12 weeks of stable methotrexate therapy with a weekly dosage of 15-25 mg. The patients averaged about 57 years old. After the first 24 weeks on randomized treatment, patients who did not have a decrease in their DAS28 of at least 1.2 units switched to the alternate regimens. The primary outcome was change in DAS28 at week 48 according to initial treatment assignment; the researchers collected 48-week DAS28 scores from 309 enrolled patients. The mean change in DAS28 from baseline at 48 weeks was a 2.12-unit reduction in the triple-therapy patients and a 2.29-unit reduction in the etanercept patients, an average 0.17-unit difference between the two treatment arms that was not statistically significant and that fell within the study’s prespecified range for noninferiority for triple therapy.

A similar percentage of patients, 27%, in each of the treatment arms switched to the alternate therapy at 24 weeks due to lack of an adequate initial response. There were also no statistically significant differences between the treatment arms in their rate of American College of Rheumatology (ACR) 20 and 50 responses at both 24 and 48 weeks.

The results showed significant differences between the treatment arms after the first 24 weeks of treatment for higher-level responses. For example, the percentage of patients achieving an ACR 70 response was 5% in the triple-therapy patients and 16% in the etanercept patients, a statistically significant difference. The rate of patients with a DAS28 score of 2.6 points or less at 24 weeks was 13% in the triple-therapy patients and 22% in those on etanercept, a significant difference.

Based on findings like these, "I would start a biologic in a patient who failed high-dose methotrexate and had poor prognostic factors and highly active disease, because at 6 months etanercept had the edge," said Dr. Edward C. Keystone, director of the Centre for Arthritis and Autoimmune Disease at Mount Sinai Hospital in Toronto, and a coinvestigator on the new study. But for all the other patients, "why not start on triple therapy first if you can switch them later if needed and the patients do well?" he asked. "The important observation is that the same percentage of patients failed in each arm. That is a huge message."

The RACAT study received no commercial support. Dr. O’Dell said that he had no disclosures. Dr. Furst has been a consultant to or received grant support from Abbott, Amgen, Bristol-Myers Squibb, and other companies. Dr. Kremer has been a consultant to or received grant support from Pfizer, Abbott, Genentech, and other companies. Dr. Keystone said that he has been a consultant to or has received research grants from Amgen, Pfizer, Merck, and other companies.

mzoler@frontlinemedcom.com On Twitter @mitchelzoler

MADRID – When rheumatoid arthritis patients fail initial treatment with methotrexate monotherapy, are they better served by a less expensive step-up treatment or the one that may better slow their radiographic progression and produce faster responses?

That seems to be the choice between step-up from methotrexate monotherapy by adding synthetic disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine and hydroxychloroquine, or by adding a tumor necrosis factor (TNF) inhibitor such as etanercept.

Mitchel L. Zoler/IMNG Medical Media

The RACAT (Rheumatoid Arthritis: Comparison of Active Therapies) trial tested those two options in 353 rheumatoid arthritis (RA) patients at 36 U.S. or Canadian sites between July 2007 and December 2010. The study’s primary endpoint, improvement in average disease activity score in 28 joints (DAS28) from baseline to 48 weeks of treatment, was similar in both treatment arms, proving the noninferiority of the triple synthetic DMARD regimen against the etanercept, biological arm, Dr. James R. O’Dell reported in a poster at the annual European Congress of Rheumatology. The results also appeared online simultaneously with Dr. O’Dell’s poster presentation (N. Engl. J. Med. 2013 June 11 [doi: 10.1056/NEJMoal1303006]).

"We showed that starting first with a TNF inhibitor or first with triple therapy resulted in the same outcomes. But costs were not the same. We [successfully] treated another 30% of patients who did not need a biologic" with the synthetic triple therapy. "And in the patients where triple therapy doesn’t work, you can change them to a biologic and they have identical outcomes, clinically by DAS28 and radiographically," compared with patients who began on etanercept added to methotrexate from the start, he said. Dr. O’Dell is chief of rheumatology at the VA Medical Center in Omaha, Neb., and professor of medicine at the University of Nebraska.

"Nothing is lost for the patient; if they don’t do well on triple therapy they can switch to a biological. The data are persuasive and the economic case is easy to make. You absolutely ought to go with triple therapy," he concluded based on the study findings.

But "it is very difficult to get physicians to buy into this" strategy, he said in an interview. TNF inhibitors such as etanercept and other biological DMARDs are "seductive," Dr. O’Dell said, because they are effective, work quickly, and appear more "targeted" than synthetic DMARDs, and they are promoted by well-financed marketing campaigns.

Dr. O’Dell conceded that the study data showed a signal of more radiographic progression with triple synthetic DMARD treatment that could potentially, over time, accrue to more substantial differences. At 48 weeks after the onset of treatment, patients on triple therapy had an average 0.54-point increase (worsening) in their van der Heijde modified Sharp score, compared with an average 0.29-point rise in the patients who received etanercept, a 0.25-point average difference in favor of etanercept that did not reach statistical significance.

But this trend toward greater radiographic progression in patients on triple therapy was consistent with the statistically significant, roughly 1-point average additional increased radiographic progression with triple therapy, compared with patients on methotrexate plus etanercept, that was seen after 2 years of follow-up in the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial (Arthritis Rheum. 2012;64:2824-35).

The TEAR study, which enrolled patients with very early RA, included a subgroup with an inadequate response to methotrexate monotherapy, and in that subgroup, patients randomized to triple therapy and those randomized to etanercept plus methotrexate had similar clinical outcomes, consistent with the new study findings.

"It’s hard to say that 1 or 2 units on the Sharp score doesn’t matter much, even if you don’t see the difference for several years," commented Dr. Daniel Furst, professor of medicine and director of the Rheumatology Clinical Research Center at the University of California, Los Angeles.

"Triple therapy is effective clinically, but it doesn’t do so well for x-rays. There are relationships between a 1 or 2 Sharp score difference and long-term outcomes. Across the board with biologics, the difference is 1 or 2 Sharp units. If one’s philosophy is to hit the RA hard and stop it, then perhaps a biologic is better," Dr. Furst commented in an interview.

But another view was that triple therapy could play a useful and cost-effective role. The new findings, along with the TEAR results, make "initial treatment of early RA with triple therapy a reasonable approach," said Dr. Joel M. Kremer, a professor of medicine at Albany (N.Y.) Medical College and director of research at the Center for Rheumatology in Albany. The only clear downside is that if triple therapy doesn’t work, the patient loses time, but that’s true for every treatment option, he noted.

"We don’t usually have the opportunity to hear the data for generic drugs" as much as for brand-name formulations, Dr. Kremer said in an interview. "Will data like this substantially change prescribing patterns? Probably not, but what might happen is that insurers may look at these data and say that patients should fail triple therapy before starting a biologic. That would be a sea change" for rheumatology, he added.

"I have always used methotrexate first, usually in combination with hydroxychloroquine," Dr. Kremer said. He has not usually also prescribed sulfasalazine, but said he would consider adding it based on the new data.

The new study enrolled patients with a DAS28 score of 4.4 or higher despite at least 12 weeks of stable methotrexate therapy with a weekly dosage of 15-25 mg. The patients averaged about 57 years old. After the first 24 weeks on randomized treatment, patients who did not have a decrease in their DAS28 of at least 1.2 units switched to the alternate regimens. The primary outcome was change in DAS28 at week 48 according to initial treatment assignment; the researchers collected 48-week DAS28 scores from 309 enrolled patients. The mean change in DAS28 from baseline at 48 weeks was a 2.12-unit reduction in the triple-therapy patients and a 2.29-unit reduction in the etanercept patients, an average 0.17-unit difference between the two treatment arms that was not statistically significant and that fell within the study’s prespecified range for noninferiority for triple therapy.

A similar percentage of patients, 27%, in each of the treatment arms switched to the alternate therapy at 24 weeks due to lack of an adequate initial response. There were also no statistically significant differences between the treatment arms in their rate of American College of Rheumatology (ACR) 20 and 50 responses at both 24 and 48 weeks.

The results showed significant differences between the treatment arms after the first 24 weeks of treatment for higher-level responses. For example, the percentage of patients achieving an ACR 70 response was 5% in the triple-therapy patients and 16% in the etanercept patients, a statistically significant difference. The rate of patients with a DAS28 score of 2.6 points or less at 24 weeks was 13% in the triple-therapy patients and 22% in those on etanercept, a significant difference.

Based on findings like these, "I would start a biologic in a patient who failed high-dose methotrexate and had poor prognostic factors and highly active disease, because at 6 months etanercept had the edge," said Dr. Edward C. Keystone, director of the Centre for Arthritis and Autoimmune Disease at Mount Sinai Hospital in Toronto, and a coinvestigator on the new study. But for all the other patients, "why not start on triple therapy first if you can switch them later if needed and the patients do well?" he asked. "The important observation is that the same percentage of patients failed in each arm. That is a huge message."

The RACAT study received no commercial support. Dr. O’Dell said that he had no disclosures. Dr. Furst has been a consultant to or received grant support from Abbott, Amgen, Bristol-Myers Squibb, and other companies. Dr. Kremer has been a consultant to or received grant support from Pfizer, Abbott, Genentech, and other companies. Dr. Keystone said that he has been a consultant to or has received research grants from Amgen, Pfizer, Merck, and other companies.

mzoler@frontlinemedcom.com On Twitter @mitchelzoler

MADRID – In newly updated recommendations for managing rheumatoid arthritis, a EULAR task force retained much from its prior 2010 version but included some significant changes such as elevating the biologic drugs tocilizumab and abatacept to the same status as tumor necrosis factor inhibitors.

The 2013 draft revision may be most notable for what stayed the same from 2010, such as keeping conventional synthetic disease-modifying antirheumatic drugs (DMARDs) as the only first-line interventions for newly diagnosed patients with rheumatoid arthritis (RA). This means the update keeps all biologic DMARDs as secondary treatments reserved for patients who fail to respond adequately to or are intolerant of methotrexate or the other conventional, synthetic DMARDs cited as first-line options: sulfasalazine, hydrochloroquine, and leflunomide.

By maintaining synthetic DMARDs – either methotrexate monotherapy or in combined regimens – as its only first-line options for treating RA, the European League Against Rheumatism (EULAR) Task Force appointed to develop the new revision broke with the 2012 RA management recommendations of the American College of Rheumatology (ACR), which cited treatment with a tumor necrosis factor (TNF) inhibitor as a first-line option, with or without combination with methotrexate, for patients with early RA, high disease activity, and poor prognostic features (Arthritis Care Res. 2012;64:625-39).

The reason to keep all biologic DMARDs as second-line drugs was the evidence that supports the "efficacy of a treat-to-target strategy when adding biologics after insufficient response to methotrexate," said Dr. Josef S. Smolen, professor of rheumatology at the Medical University of Vienna, who presented the draft update during a session at the annual European Congress of Rheumatology. Dr. Smolen stressed that although the EULAR-appointed, 33-member update task force had completed all their votes to approve the draft recommendations, the update was still subject to further review and change before its eventual publication.

The new draft "does not advocate use of biologics as first DMARD strategies because the treat-to-target approach will lead to a similar overall outcome while avoiding the overtreatment of 20%-50% of patients with early RA," Dr. Smolen explained. The revision also does not endorse monotherapy with a TNF inhibitor or any other type of biologic DMARD.

Another major break from the past in the new revision is its leveling of the role for tocilizumab (Actemra) and abatacept (Orencia) alongside the several TNF inhibitor DMARDs now on the worldwide market. Last year’s ACR recommendations specified anti-TNF drugs as an option for initial therapy of patients with high disease activity and poor prognostic features, as well as low disease activity patients who get inadequate benefit from synthetic DMARDs. In the ACR recommendations, abatacept as well as rituximab (Rituxan) fell lower in the management algorithm, while tocilizumab was completely off the page.

Not only do the new EULAR recommendations place tocilizumab and abatacept on the same level as the TNF inhibitors, the EULAR draft further singles out tocilizumab as the "preferred agent" for patients who must receive a biologic DMARD as monotherapy rather than the preferred way, in combination with methotrexate. "Preference is given to combining all biologicals with methotrexate," Dr. Smolen said. The revision also cites rituximab as another biologic DMARD to consider, but it’s not ranked as high as the others.

In another change from 2010, the task force specially noted the potential benefit from using multiple conventional synthetic DMARDs for initial treatment. "The 2013 task force reiterates the evidence-based view that conventional synthetic DMARD monotherpy is effective, but based on some newer trial data on conventional synthetic DMARD combination therapy, the task force more explicitly endorses combination of conventional synthetic DMARDs early on. Preference to combination is not given because of possible limitations in the design of these trials and conflicting trial data."

The 2013 recommendations also specify a role for tofacitinib (Xeljanz), which received U.S. marketing approval late last year. Dr. Smolen highlighted that the task force reached a consensus on how to fit tofacitinib into the treatment algorithm in early April, before the European Medicines Agency denied the drug European marketing approval in late April. Despite the drug being turned down as a treatment option for European patients, "the task force was convinced of the clinical, functional, and structural efficacy of tofacitinib based on available evidence." However, citing a possibly higher risk for flare of herpes zoster, compared with biologic DMARDs, the task force said that tofacitinib should be used only in patients who had failed at least one biologic drug and "preferably two" until more experience and registry data became available.

Dr. Smolen said he has been a consultant to, a speaker for, or has received grant support from 14 pharmaceutical companies. He also said he served as the principal investigator for seven trials that assessed six different biologic agents for the treatment of rheumatoid arthritis.

Summary of EULAR’s 2013 RA management recommendations

The draft 2013 EULAR rheumatoid arthritis management recommendations includes three overarching principles and 14 recommendations. Here is a summary of the draft recommendations:

1. Therapy with DMARDs should start as soon as rheumatoid arthritis is diagnosed.

2. Treatment should aim to achieve remission or low disease activity.

3. Monitoring should be frequent, and if there is no improvement after a maximum of 3 months or if the target has not been reached by a maximum of 6 months, treatment should be adjusted.

4. Methotrexate should be part of the first treatment strategy.

5. When methotrexate is contraindicated or not tolerated, consider sulfasalazine or leflunomide as part of the treatment regimen.

6. Early treatment with a combination of conventional synthetic DMARDs is a reasonable alternative to initial methotrexate monotherapy.

7. Consider adding a low-dose glucocorticoid as part of initial treatment for up to 6 months; taper down as rapidly as clinically feasible.

8. If the treatment target is not reached, consider changing to another synthetic DMARD regimen; if the patient has poor prognostic features, consider adding a biological DMARD.

9. If a patient does not respond adequately to treatment with conventional, synthetic DMARDs – with or without concurrent treatment with a glucocorticoid – a biological DMARD should be started along with methotrexate. The biological DMARD could be a TNF inhibitor, abatacept, or tocilizumab.

10. Patients who fail to adequately respond to a biological DMARD should be switched to another biological DMARD. Patients who fail a first TNF inhibitor may be switched to a different TNF inhibitor.

11. Treatment with tofacitinib can be considered after patients fail treatment with biological DMARDs.

12. For patients in persistent remission, first taper down the corticosteroid dosage. If remission persists consider tapering down treatment with any biological DMARD, especially if the patient is also receiving one or more synthetic DMARDs.

13. In patients with sustained, long-term remission, consider tapering down the dosage of conventional, synthetic DMARDs as a shared decision between the patient and physician.

14. When adjusting therapy, take into account progression of structural damage, comorbidities, and safety issues, as well as disease activity.

Source: Dr. Smolen

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

MADRID – In newly updated recommendations for managing rheumatoid arthritis, a EULAR task force retained much from its prior 2010 version but included some significant changes such as elevating the biologic drugs tocilizumab and abatacept to the same status as tumor necrosis factor inhibitors.

The 2013 draft revision may be most notable for what stayed the same from 2010, such as keeping conventional synthetic disease-modifying antirheumatic drugs (DMARDs) as the only first-line interventions for newly diagnosed patients with rheumatoid arthritis (RA). This means the update keeps all biologic DMARDs as secondary treatments reserved for patients who fail to respond adequately to or are intolerant of methotrexate or the other conventional, synthetic DMARDs cited as first-line options: sulfasalazine, hydrochloroquine, and leflunomide.

By maintaining synthetic DMARDs – either methotrexate monotherapy or in combined regimens – as its only first-line options for treating RA, the European League Against Rheumatism (EULAR) Task Force appointed to develop the new revision broke with the 2012 RA management recommendations of the American College of Rheumatology (ACR), which cited treatment with a tumor necrosis factor (TNF) inhibitor as a first-line option, with or without combination with methotrexate, for patients with early RA, high disease activity, and poor prognostic features (Arthritis Care Res. 2012;64:625-39).

The reason to keep all biologic DMARDs as second-line drugs was the evidence that supports the "efficacy of a treat-to-target strategy when adding biologics after insufficient response to methotrexate," said Dr. Josef S. Smolen, professor of rheumatology at the Medical University of Vienna, who presented the draft update during a session at the annual European Congress of Rheumatology. Dr. Smolen stressed that although the EULAR-appointed, 33-member update task force had completed all their votes to approve the draft recommendations, the update was still subject to further review and change before its eventual publication.

The new draft "does not advocate use of biologics as first DMARD strategies because the treat-to-target approach will lead to a similar overall outcome while avoiding the overtreatment of 20%-50% of patients with early RA," Dr. Smolen explained. The revision also does not endorse monotherapy with a TNF inhibitor or any other type of biologic DMARD.

Another major break from the past in the new revision is its leveling of the role for tocilizumab (Actemra) and abatacept (Orencia) alongside the several TNF inhibitor DMARDs now on the worldwide market. Last year’s ACR recommendations specified anti-TNF drugs as an option for initial therapy of patients with high disease activity and poor prognostic features, as well as low disease activity patients who get inadequate benefit from synthetic DMARDs. In the ACR recommendations, abatacept as well as rituximab (Rituxan) fell lower in the management algorithm, while tocilizumab was completely off the page.

Not only do the new EULAR recommendations place tocilizumab and abatacept on the same level as the TNF inhibitors, the EULAR draft further singles out tocilizumab as the "preferred agent" for patients who must receive a biologic DMARD as monotherapy rather than the preferred way, in combination with methotrexate. "Preference is given to combining all biologicals with methotrexate," Dr. Smolen said. The revision also cites rituximab as another biologic DMARD to consider, but it’s not ranked as high as the others.

In another change from 2010, the task force specially noted the potential benefit from using multiple conventional synthetic DMARDs for initial treatment. "The 2013 task force reiterates the evidence-based view that conventional synthetic DMARD monotherpy is effective, but based on some newer trial data on conventional synthetic DMARD combination therapy, the task force more explicitly endorses combination of conventional synthetic DMARDs early on. Preference to combination is not given because of possible limitations in the design of these trials and conflicting trial data."

The 2013 recommendations also specify a role for tofacitinib (Xeljanz), which received U.S. marketing approval late last year. Dr. Smolen highlighted that the task force reached a consensus on how to fit tofacitinib into the treatment algorithm in early April, before the European Medicines Agency denied the drug European marketing approval in late April. Despite the drug being turned down as a treatment option for European patients, "the task force was convinced of the clinical, functional, and structural efficacy of tofacitinib based on available evidence." However, citing a possibly higher risk for flare of herpes zoster, compared with biologic DMARDs, the task force said that tofacitinib should be used only in patients who had failed at least one biologic drug and "preferably two" until more experience and registry data became available.

Dr. Smolen said he has been a consultant to, a speaker for, or has received grant support from 14 pharmaceutical companies. He also said he served as the principal investigator for seven trials that assessed six different biologic agents for the treatment of rheumatoid arthritis.

Summary of EULAR’s 2013 RA management recommendations

The draft 2013 EULAR rheumatoid arthritis management recommendations includes three overarching principles and 14 recommendations. Here is a summary of the draft recommendations:

1. Therapy with DMARDs should start as soon as rheumatoid arthritis is diagnosed.

2. Treatment should aim to achieve remission or low disease activity.

3. Monitoring should be frequent, and if there is no improvement after a maximum of 3 months or if the target has not been reached by a maximum of 6 months, treatment should be adjusted.

4. Methotrexate should be part of the first treatment strategy.

5. When methotrexate is contraindicated or not tolerated, consider sulfasalazine or leflunomide as part of the treatment regimen.

6. Early treatment with a combination of conventional synthetic DMARDs is a reasonable alternative to initial methotrexate monotherapy.

7. Consider adding a low-dose glucocorticoid as part of initial treatment for up to 6 months; taper down as rapidly as clinically feasible.

8. If the treatment target is not reached, consider changing to another synthetic DMARD regimen; if the patient has poor prognostic features, consider adding a biological DMARD.

9. If a patient does not respond adequately to treatment with conventional, synthetic DMARDs – with or without concurrent treatment with a glucocorticoid – a biological DMARD should be started along with methotrexate. The biological DMARD could be a TNF inhibitor, abatacept, or tocilizumab.

10. Patients who fail to adequately respond to a biological DMARD should be switched to another biological DMARD. Patients who fail a first TNF inhibitor may be switched to a different TNF inhibitor.

11. Treatment with tofacitinib can be considered after patients fail treatment with biological DMARDs.

12. For patients in persistent remission, first taper down the corticosteroid dosage. If remission persists consider tapering down treatment with any biological DMARD, especially if the patient is also receiving one or more synthetic DMARDs.

13. In patients with sustained, long-term remission, consider tapering down the dosage of conventional, synthetic DMARDs as a shared decision between the patient and physician.

14. When adjusting therapy, take into account progression of structural damage, comorbidities, and safety issues, as well as disease activity.

Source: Dr. Smolen

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

MADRID – In newly updated recommendations for managing rheumatoid arthritis, a EULAR task force retained much from its prior 2010 version but included some significant changes such as elevating the biologic drugs tocilizumab and abatacept to the same status as tumor necrosis factor inhibitors.

The 2013 draft revision may be most notable for what stayed the same from 2010, such as keeping conventional synthetic disease-modifying antirheumatic drugs (DMARDs) as the only first-line interventions for newly diagnosed patients with rheumatoid arthritis (RA). This means the update keeps all biologic DMARDs as secondary treatments reserved for patients who fail to respond adequately to or are intolerant of methotrexate or the other conventional, synthetic DMARDs cited as first-line options: sulfasalazine, hydrochloroquine, and leflunomide.

By maintaining synthetic DMARDs – either methotrexate monotherapy or in combined regimens – as its only first-line options for treating RA, the European League Against Rheumatism (EULAR) Task Force appointed to develop the new revision broke with the 2012 RA management recommendations of the American College of Rheumatology (ACR), which cited treatment with a tumor necrosis factor (TNF) inhibitor as a first-line option, with or without combination with methotrexate, for patients with early RA, high disease activity, and poor prognostic features (Arthritis Care Res. 2012;64:625-39).

The reason to keep all biologic DMARDs as second-line drugs was the evidence that supports the "efficacy of a treat-to-target strategy when adding biologics after insufficient response to methotrexate," said Dr. Josef S. Smolen, professor of rheumatology at the Medical University of Vienna, who presented the draft update during a session at the annual European Congress of Rheumatology. Dr. Smolen stressed that although the EULAR-appointed, 33-member update task force had completed all their votes to approve the draft recommendations, the update was still subject to further review and change before its eventual publication.

The new draft "does not advocate use of biologics as first DMARD strategies because the treat-to-target approach will lead to a similar overall outcome while avoiding the overtreatment of 20%-50% of patients with early RA," Dr. Smolen explained. The revision also does not endorse monotherapy with a TNF inhibitor or any other type of biologic DMARD.

Another major break from the past in the new revision is its leveling of the role for tocilizumab (Actemra) and abatacept (Orencia) alongside the several TNF inhibitor DMARDs now on the worldwide market. Last year’s ACR recommendations specified anti-TNF drugs as an option for initial therapy of patients with high disease activity and poor prognostic features, as well as low disease activity patients who get inadequate benefit from synthetic DMARDs. In the ACR recommendations, abatacept as well as rituximab (Rituxan) fell lower in the management algorithm, while tocilizumab was completely off the page.

Not only do the new EULAR recommendations place tocilizumab and abatacept on the same level as the TNF inhibitors, the EULAR draft further singles out tocilizumab as the "preferred agent" for patients who must receive a biologic DMARD as monotherapy rather than the preferred way, in combination with methotrexate. "Preference is given to combining all biologicals with methotrexate," Dr. Smolen said. The revision also cites rituximab as another biologic DMARD to consider, but it’s not ranked as high as the others.

In another change from 2010, the task force specially noted the potential benefit from using multiple conventional synthetic DMARDs for initial treatment. "The 2013 task force reiterates the evidence-based view that conventional synthetic DMARD monotherpy is effective, but based on some newer trial data on conventional synthetic DMARD combination therapy, the task force more explicitly endorses combination of conventional synthetic DMARDs early on. Preference to combination is not given because of possible limitations in the design of these trials and conflicting trial data."

The 2013 recommendations also specify a role for tofacitinib (Xeljanz), which received U.S. marketing approval late last year. Dr. Smolen highlighted that the task force reached a consensus on how to fit tofacitinib into the treatment algorithm in early April, before the European Medicines Agency denied the drug European marketing approval in late April. Despite the drug being turned down as a treatment option for European patients, "the task force was convinced of the clinical, functional, and structural efficacy of tofacitinib based on available evidence." However, citing a possibly higher risk for flare of herpes zoster, compared with biologic DMARDs, the task force said that tofacitinib should be used only in patients who had failed at least one biologic drug and "preferably two" until more experience and registry data became available.

Dr. Smolen said he has been a consultant to, a speaker for, or has received grant support from 14 pharmaceutical companies. He also said he served as the principal investigator for seven trials that assessed six different biologic agents for the treatment of rheumatoid arthritis.

Summary of EULAR’s 2013 RA management recommendations

The draft 2013 EULAR rheumatoid arthritis management recommendations includes three overarching principles and 14 recommendations. Here is a summary of the draft recommendations:

1. Therapy with DMARDs should start as soon as rheumatoid arthritis is diagnosed.

2. Treatment should aim to achieve remission or low disease activity.

3. Monitoring should be frequent, and if there is no improvement after a maximum of 3 months or if the target has not been reached by a maximum of 6 months, treatment should be adjusted.

4. Methotrexate should be part of the first treatment strategy.

5. When methotrexate is contraindicated or not tolerated, consider sulfasalazine or leflunomide as part of the treatment regimen.

6. Early treatment with a combination of conventional synthetic DMARDs is a reasonable alternative to initial methotrexate monotherapy.

7. Consider adding a low-dose glucocorticoid as part of initial treatment for up to 6 months; taper down as rapidly as clinically feasible.

8. If the treatment target is not reached, consider changing to another synthetic DMARD regimen; if the patient has poor prognostic features, consider adding a biological DMARD.

9. If a patient does not respond adequately to treatment with conventional, synthetic DMARDs – with or without concurrent treatment with a glucocorticoid – a biological DMARD should be started along with methotrexate. The biological DMARD could be a TNF inhibitor, abatacept, or tocilizumab.

10. Patients who fail to adequately respond to a biological DMARD should be switched to another biological DMARD. Patients who fail a first TNF inhibitor may be switched to a different TNF inhibitor.

11. Treatment with tofacitinib can be considered after patients fail treatment with biological DMARDs.

12. For patients in persistent remission, first taper down the corticosteroid dosage. If remission persists consider tapering down treatment with any biological DMARD, especially if the patient is also receiving one or more synthetic DMARDs.

13. In patients with sustained, long-term remission, consider tapering down the dosage of conventional, synthetic DMARDs as a shared decision between the patient and physician.

14. When adjusting therapy, take into account progression of structural damage, comorbidities, and safety issues, as well as disease activity.

Source: Dr. Smolen

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

Recent research has suggested that tumor necrosis factor inhibitors can significantly reduce diabetes risk in people with rheumatoid arthritis.

Dr. Siri Lillegraven of Diakonhjemmet Hospital in Oslo presented results from the CORRONA (Consortium of Rheumatology Researchers of North America) study, which Dr. Lillegraven, its lead author, called "the first large study to find the same association" at the annual European Congress of Rheumatology. The study used CORRONA registry data from 22,943 patients and about 22,000 RA treatment regimens with a mean duration between 1.5 and 2.4 years.

Dr. Lillegraven and her colleagues found an adjusted hazard ratio for type 2 diabetes of 0.35 for TNF inhibitors (95% confidence interval, 0.13-0.91), compared with a reference group of non-methotrexate, non-hydroxychloroquine, nonbiologic disease-modifying antirheumatic drugs such as cyclosporine, sulfasalazine, and leflunomide. The DMARDs hydroxychloroquine and methotrexate were separately compared with this reference group.

"It was a statistically significant finding, and the model was adjusted for differences between patients who received TNF inhibitors and the patients who received the comparator drugs," Dr. Lillegraven said in an interview.

One of Dr. Lillegraven’s coauthors on the study, Dr. Daniel Solomon of Brigham and Women’s Hospital in Boston earlier reported a lower risk of type 2 diabetes for individuals taking TNF inhibitors or hydroxychloroquine, compared with nonbiologic DMARDs (JAMA 2011;305:2525-31).

In that study, which enrolled about 14,000 patients and evaluated about 22,000 treatment episodes, the multivariate adjusted hazard ratio for diabetes was 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, compared with other nonbiologic DMARDs. The effect was even greater for hydroxychloroquine, compared with other nonbiologics (hazard ratio, 0.54; 95% CI, 0.36-0.80).

Dr. Lillegraven and her colleagues saw a similar effect size for hydroxychloroquine, compared with the nonbiologic DMARDs, but this did not reach statistical significance.

As both studies were observational in design, Dr. Lillegraven noted, the results do not carry the weight of randomized, controlled trial findings. "We would have loved to have a clinical trial that confirmed the findings," she said, adding that designing such a trial would be difficult. "The outcome is relatively rare, and you will not likely get enough diabetes outcomes to be able to conclude whether an exposure had an effect." In Dr. Lillegraven and her colleagues’ study, for example, only 84 incident cases of diabetes occurred.

Last year, investigators reported that TNF inhibitors were associated with a halving of diabetes risk, compared with RA patients who had never used them (HR, 0.49; 95% CI 0.24-0.99), in a cohort of 1,587 RA patients without diabetes at enrollment who were followed for 3-4 years (Arthritis Care Res. 2012;64:215-21), and several studies have suggested a relationship between the biologic pathways that TNF inhibitors affect and diabetes.

Dr. Lillegraven also analyzed the impact of body-mass index (BMI) and steroid dosage on diabetes incidence in these patients. Those with a BMI of more than 30 kg/m² had a statistically significant sixfold increased rate of incident diabetes, compared with patients with a BMI of less than 25 kg/m². Patients with a BMI of 25-30 kg/m² had a significant, nearly twofold increased rate. Patients who received a steroid dose of at least 7.5 mg/day had a statistically significant, twofold increased diabetes incidence, compared with patients who did not receive any steroid treatment.

Dr. Lillegraven said that her study’s findings, added to the earlier findings, support "a potential for tailoring treatment in high-risk individuals." But it is still too early to draw any definite conclusions regarding how this should be carried out in the clinic, she cautioned.

Dr. Lillegraven declared no conflicts of interest relevant to her study. Dr. Solomon declared unpaid consultancies for Pfizer and Novartis. Three other coauthors reported financial relationships with pharmaceutical firms and CORRONA, a database registry for rheumatologic diseases; one is an employee of CORRONA.

Recent research has suggested that tumor necrosis factor inhibitors can significantly reduce diabetes risk in people with rheumatoid arthritis.

Dr. Siri Lillegraven of Diakonhjemmet Hospital in Oslo presented results from the CORRONA (Consortium of Rheumatology Researchers of North America) study, which Dr. Lillegraven, its lead author, called "the first large study to find the same association" at the annual European Congress of Rheumatology. The study used CORRONA registry data from 22,943 patients and about 22,000 RA treatment regimens with a mean duration between 1.5 and 2.4 years.

Dr. Lillegraven and her colleagues found an adjusted hazard ratio for type 2 diabetes of 0.35 for TNF inhibitors (95% confidence interval, 0.13-0.91), compared with a reference group of non-methotrexate, non-hydroxychloroquine, nonbiologic disease-modifying antirheumatic drugs such as cyclosporine, sulfasalazine, and leflunomide. The DMARDs hydroxychloroquine and methotrexate were separately compared with this reference group.

"It was a statistically significant finding, and the model was adjusted for differences between patients who received TNF inhibitors and the patients who received the comparator drugs," Dr. Lillegraven said in an interview.

One of Dr. Lillegraven’s coauthors on the study, Dr. Daniel Solomon of Brigham and Women’s Hospital in Boston earlier reported a lower risk of type 2 diabetes for individuals taking TNF inhibitors or hydroxychloroquine, compared with nonbiologic DMARDs (JAMA 2011;305:2525-31).

In that study, which enrolled about 14,000 patients and evaluated about 22,000 treatment episodes, the multivariate adjusted hazard ratio for diabetes was 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, compared with other nonbiologic DMARDs. The effect was even greater for hydroxychloroquine, compared with other nonbiologics (hazard ratio, 0.54; 95% CI, 0.36-0.80).

Dr. Lillegraven and her colleagues saw a similar effect size for hydroxychloroquine, compared with the nonbiologic DMARDs, but this did not reach statistical significance.

As both studies were observational in design, Dr. Lillegraven noted, the results do not carry the weight of randomized, controlled trial findings. "We would have loved to have a clinical trial that confirmed the findings," she said, adding that designing such a trial would be difficult. "The outcome is relatively rare, and you will not likely get enough diabetes outcomes to be able to conclude whether an exposure had an effect." In Dr. Lillegraven and her colleagues’ study, for example, only 84 incident cases of diabetes occurred.

Last year, investigators reported that TNF inhibitors were associated with a halving of diabetes risk, compared with RA patients who had never used them (HR, 0.49; 95% CI 0.24-0.99), in a cohort of 1,587 RA patients without diabetes at enrollment who were followed for 3-4 years (Arthritis Care Res. 2012;64:215-21), and several studies have suggested a relationship between the biologic pathways that TNF inhibitors affect and diabetes.

Dr. Lillegraven also analyzed the impact of body-mass index (BMI) and steroid dosage on diabetes incidence in these patients. Those with a BMI of more than 30 kg/m² had a statistically significant sixfold increased rate of incident diabetes, compared with patients with a BMI of less than 25 kg/m². Patients with a BMI of 25-30 kg/m² had a significant, nearly twofold increased rate. Patients who received a steroid dose of at least 7.5 mg/day had a statistically significant, twofold increased diabetes incidence, compared with patients who did not receive any steroid treatment.

Dr. Lillegraven said that her study’s findings, added to the earlier findings, support "a potential for tailoring treatment in high-risk individuals." But it is still too early to draw any definite conclusions regarding how this should be carried out in the clinic, she cautioned.

Dr. Lillegraven declared no conflicts of interest relevant to her study. Dr. Solomon declared unpaid consultancies for Pfizer and Novartis. Three other coauthors reported financial relationships with pharmaceutical firms and CORRONA, a database registry for rheumatologic diseases; one is an employee of CORRONA.

Recent research has suggested that tumor necrosis factor inhibitors can significantly reduce diabetes risk in people with rheumatoid arthritis.

Dr. Siri Lillegraven of Diakonhjemmet Hospital in Oslo presented results from the CORRONA (Consortium of Rheumatology Researchers of North America) study, which Dr. Lillegraven, its lead author, called "the first large study to find the same association" at the annual European Congress of Rheumatology. The study used CORRONA registry data from 22,943 patients and about 22,000 RA treatment regimens with a mean duration between 1.5 and 2.4 years.

Dr. Lillegraven and her colleagues found an adjusted hazard ratio for type 2 diabetes of 0.35 for TNF inhibitors (95% confidence interval, 0.13-0.91), compared with a reference group of non-methotrexate, non-hydroxychloroquine, nonbiologic disease-modifying antirheumatic drugs such as cyclosporine, sulfasalazine, and leflunomide. The DMARDs hydroxychloroquine and methotrexate were separately compared with this reference group.

"It was a statistically significant finding, and the model was adjusted for differences between patients who received TNF inhibitors and the patients who received the comparator drugs," Dr. Lillegraven said in an interview.

One of Dr. Lillegraven’s coauthors on the study, Dr. Daniel Solomon of Brigham and Women’s Hospital in Boston earlier reported a lower risk of type 2 diabetes for individuals taking TNF inhibitors or hydroxychloroquine, compared with nonbiologic DMARDs (JAMA 2011;305:2525-31).

In that study, which enrolled about 14,000 patients and evaluated about 22,000 treatment episodes, the multivariate adjusted hazard ratio for diabetes was 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, compared with other nonbiologic DMARDs. The effect was even greater for hydroxychloroquine, compared with other nonbiologics (hazard ratio, 0.54; 95% CI, 0.36-0.80).

Dr. Lillegraven and her colleagues saw a similar effect size for hydroxychloroquine, compared with the nonbiologic DMARDs, but this did not reach statistical significance.

As both studies were observational in design, Dr. Lillegraven noted, the results do not carry the weight of randomized, controlled trial findings. "We would have loved to have a clinical trial that confirmed the findings," she said, adding that designing such a trial would be difficult. "The outcome is relatively rare, and you will not likely get enough diabetes outcomes to be able to conclude whether an exposure had an effect." In Dr. Lillegraven and her colleagues’ study, for example, only 84 incident cases of diabetes occurred.

Last year, investigators reported that TNF inhibitors were associated with a halving of diabetes risk, compared with RA patients who had never used them (HR, 0.49; 95% CI 0.24-0.99), in a cohort of 1,587 RA patients without diabetes at enrollment who were followed for 3-4 years (Arthritis Care Res. 2012;64:215-21), and several studies have suggested a relationship between the biologic pathways that TNF inhibitors affect and diabetes.

Dr. Lillegraven also analyzed the impact of body-mass index (BMI) and steroid dosage on diabetes incidence in these patients. Those with a BMI of more than 30 kg/m² had a statistically significant sixfold increased rate of incident diabetes, compared with patients with a BMI of less than 25 kg/m². Patients with a BMI of 25-30 kg/m² had a significant, nearly twofold increased rate. Patients who received a steroid dose of at least 7.5 mg/day had a statistically significant, twofold increased diabetes incidence, compared with patients who did not receive any steroid treatment.

Dr. Lillegraven said that her study’s findings, added to the earlier findings, support "a potential for tailoring treatment in high-risk individuals." But it is still too early to draw any definite conclusions regarding how this should be carried out in the clinic, she cautioned.

Dr. Lillegraven declared no conflicts of interest relevant to her study. Dr. Solomon declared unpaid consultancies for Pfizer and Novartis. Three other coauthors reported financial relationships with pharmaceutical firms and CORRONA, a database registry for rheumatologic diseases; one is an employee of CORRONA.

Recent research has suggested that tumor necrosis factor inhibitors can significantly reduce diabetes risk in people with rheumatoid arthritis.

Dr. Siri Lillegraven of Diakonhjemmet Hospital in Oslo presented results from the CORRONA (Consortium of Rheumatology Researchers of North America) study, which Dr. Lillegraven, its lead author, called "the first large study to find the same association" at the annual European Congress of Rheumatology. The study used CORRONA registry data from 22,943 patients and about 22,000 RA treatment regimens with a mean duration between 1.5 and 2.4 years.

Dr. Lillegraven and her colleagues found an adjusted hazard ratio for type 2 diabetes of 0.35 for TNF inhibitors (95% confidence interval, 0.13-0.91), compared with a reference group of non-methotrexate, non-hydroxychloroquine, nonbiologic disease-modifying antirheumatic drugs such as cyclosporine, sulfasalazine, and leflunomide. The DMARDs hydroxychloroquine and methotrexate were separately compared with this reference group.

"It was a statistically significant finding, and the model was adjusted for differences between patients who received TNF inhibitors and the patients who received the comparator drugs," Dr. Lillegraven said in an interview.

One of Dr. Lillegraven’s coauthors on the study, Dr. Daniel Solomon of Brigham and Women’s Hospital in Boston earlier reported a lower risk of type 2 diabetes for individuals taking TNF inhibitors or hydroxychloroquine, compared with nonbiologic DMARDs (JAMA 2011;305:2525-31).

In that study, which enrolled about 14,000 patients and evaluated about 22,000 treatment episodes, the multivariate adjusted hazard ratio for diabetes was 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, compared with other nonbiologic DMARDs. The effect was even greater for hydroxychloroquine, compared with other nonbiologics (hazard ratio, 0.54; 95% CI, 0.36-0.80).

Dr. Lillegraven and her colleagues saw a similar effect size for hydroxychloroquine, compared with the nonbiologic DMARDs, but this did not reach statistical significance.

As both studies were observational in design, Dr. Lillegraven noted, the results do not carry the weight of randomized, controlled trial findings. "We would have loved to have a clinical trial that confirmed the findings," she said, adding that designing such a trial would be difficult. "The outcome is relatively rare, and you will not likely get enough diabetes outcomes to be able to conclude whether an exposure had an effect." In Dr. Lillegraven and her colleagues’ study, for example, only 84 incident cases of diabetes occurred.

Last year, investigators reported that TNF inhibitors were associated with a halving of diabetes risk, compared with RA patients who had never used them (HR, 0.49; 95% CI 0.24-0.99), in a cohort of 1,587 RA patients without diabetes at enrollment who were followed for 3-4 years (Arthritis Care Res. 2012;64:215-21), and several studies have suggested a relationship between the biologic pathways that TNF inhibitors affect and diabetes.

Dr. Lillegraven also analyzed the impact of body-mass index (BMI) and steroid dosage on diabetes incidence in these patients. Those with a BMI of more than 30 kg/m² had a statistically significant sixfold increased rate of incident diabetes, compared with patients with a BMI of less than 25 kg/m². Patients with a BMI of 25-30 kg/m² had a significant, nearly twofold increased rate. Patients who received a steroid dose of at least 7.5 mg/day had a statistically significant, twofold increased diabetes incidence, compared with patients who did not receive any steroid treatment.

Dr. Lillegraven said that her study’s findings, added to the earlier findings, support "a potential for tailoring treatment in high-risk individuals." But it is still too early to draw any definite conclusions regarding how this should be carried out in the clinic, she cautioned.

Dr. Lillegraven declared no conflicts of interest relevant to her study. Dr. Solomon declared unpaid consultancies for Pfizer and Novartis. Three other coauthors reported financial relationships with pharmaceutical firms and CORRONA, a database registry for rheumatologic diseases; one is an employee of CORRONA.

Recent research has suggested that tumor necrosis factor inhibitors can significantly reduce diabetes risk in people with rheumatoid arthritis.

Dr. Siri Lillegraven of Diakonhjemmet Hospital in Oslo presented results from the CORRONA (Consortium of Rheumatology Researchers of North America) study, which Dr. Lillegraven, its lead author, called "the first large study to find the same association" at the annual European Congress of Rheumatology. The study used CORRONA registry data from 22,943 patients and about 22,000 RA treatment regimens with a mean duration between 1.5 and 2.4 years.

Dr. Lillegraven and her colleagues found an adjusted hazard ratio for type 2 diabetes of 0.35 for TNF inhibitors (95% confidence interval, 0.13-0.91), compared with a reference group of non-methotrexate, non-hydroxychloroquine, nonbiologic disease-modifying antirheumatic drugs such as cyclosporine, sulfasalazine, and leflunomide. The DMARDs hydroxychloroquine and methotrexate were separately compared with this reference group.

"It was a statistically significant finding, and the model was adjusted for differences between patients who received TNF inhibitors and the patients who received the comparator drugs," Dr. Lillegraven said in an interview.

One of Dr. Lillegraven’s coauthors on the study, Dr. Daniel Solomon of Brigham and Women’s Hospital in Boston earlier reported a lower risk of type 2 diabetes for individuals taking TNF inhibitors or hydroxychloroquine, compared with nonbiologic DMARDs (JAMA 2011;305:2525-31).

In that study, which enrolled about 14,000 patients and evaluated about 22,000 treatment episodes, the multivariate adjusted hazard ratio for diabetes was 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, compared with other nonbiologic DMARDs. The effect was even greater for hydroxychloroquine, compared with other nonbiologics (hazard ratio, 0.54; 95% CI, 0.36-0.80).

Dr. Lillegraven and her colleagues saw a similar effect size for hydroxychloroquine, compared with the nonbiologic DMARDs, but this did not reach statistical significance.

As both studies were observational in design, Dr. Lillegraven noted, the results do not carry the weight of randomized, controlled trial findings. "We would have loved to have a clinical trial that confirmed the findings," she said, adding that designing such a trial would be difficult. "The outcome is relatively rare, and you will not likely get enough diabetes outcomes to be able to conclude whether an exposure had an effect." In Dr. Lillegraven and her colleagues’ study, for example, only 84 incident cases of diabetes occurred.

Last year, investigators reported that TNF inhibitors were associated with a halving of diabetes risk, compared with RA patients who had never used them (HR, 0.49; 95% CI 0.24-0.99), in a cohort of 1,587 RA patients without diabetes at enrollment who were followed for 3-4 years (Arthritis Care Res. 2012;64:215-21), and several studies have suggested a relationship between the biologic pathways that TNF inhibitors affect and diabetes.

Dr. Lillegraven also analyzed the impact of body-mass index (BMI) and steroid dosage on diabetes incidence in these patients. Those with a BMI of more than 30 kg/m² had a statistically significant sixfold increased rate of incident diabetes, compared with patients with a BMI of less than 25 kg/m². Patients with a BMI of 25-30 kg/m² had a significant, nearly twofold increased rate. Patients who received a steroid dose of at least 7.5 mg/day had a statistically significant, twofold increased diabetes incidence, compared with patients who did not receive any steroid treatment.

Dr. Lillegraven said that her study’s findings, added to the earlier findings, support "a potential for tailoring treatment in high-risk individuals." But it is still too early to draw any definite conclusions regarding how this should be carried out in the clinic, she cautioned.

Dr. Lillegraven declared no conflicts of interest relevant to her study. Dr. Solomon declared unpaid consultancies for Pfizer and Novartis. Three other coauthors reported financial relationships with pharmaceutical firms and CORRONA, a database registry for rheumatologic diseases; one is an employee of CORRONA.

Recent research has suggested that tumor necrosis factor inhibitors can significantly reduce diabetes risk in people with rheumatoid arthritis.

Dr. Siri Lillegraven of Diakonhjemmet Hospital in Oslo presented results from the CORRONA (Consortium of Rheumatology Researchers of North America) study, which Dr. Lillegraven, its lead author, called "the first large study to find the same association" at the annual European Congress of Rheumatology. The study used CORRONA registry data from 22,943 patients and about 22,000 RA treatment regimens with a mean duration between 1.5 and 2.4 years.

Dr. Lillegraven and her colleagues found an adjusted hazard ratio for type 2 diabetes of 0.35 for TNF inhibitors (95% confidence interval, 0.13-0.91), compared with a reference group of non-methotrexate, non-hydroxychloroquine, nonbiologic disease-modifying antirheumatic drugs such as cyclosporine, sulfasalazine, and leflunomide. The DMARDs hydroxychloroquine and methotrexate were separately compared with this reference group.

"It was a statistically significant finding, and the model was adjusted for differences between patients who received TNF inhibitors and the patients who received the comparator drugs," Dr. Lillegraven said in an interview.

One of Dr. Lillegraven’s coauthors on the study, Dr. Daniel Solomon of Brigham and Women’s Hospital in Boston earlier reported a lower risk of type 2 diabetes for individuals taking TNF inhibitors or hydroxychloroquine, compared with nonbiologic DMARDs (JAMA 2011;305:2525-31).

In that study, which enrolled about 14,000 patients and evaluated about 22,000 treatment episodes, the multivariate adjusted hazard ratio for diabetes was 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, compared with other nonbiologic DMARDs. The effect was even greater for hydroxychloroquine, compared with other nonbiologics (hazard ratio, 0.54; 95% CI, 0.36-0.80).

Dr. Lillegraven and her colleagues saw a similar effect size for hydroxychloroquine, compared with the nonbiologic DMARDs, but this did not reach statistical significance.

As both studies were observational in design, Dr. Lillegraven noted, the results do not carry the weight of randomized, controlled trial findings. "We would have loved to have a clinical trial that confirmed the findings," she said, adding that designing such a trial would be difficult. "The outcome is relatively rare, and you will not likely get enough diabetes outcomes to be able to conclude whether an exposure had an effect." In Dr. Lillegraven and her colleagues’ study, for example, only 84 incident cases of diabetes occurred.

Last year, investigators reported that TNF inhibitors were associated with a halving of diabetes risk, compared with RA patients who had never used them (HR, 0.49; 95% CI 0.24-0.99), in a cohort of 1,587 RA patients without diabetes at enrollment who were followed for 3-4 years (Arthritis Care Res. 2012;64:215-21), and several studies have suggested a relationship between the biologic pathways that TNF inhibitors affect and diabetes.

Dr. Lillegraven also analyzed the impact of body-mass index (BMI) and steroid dosage on diabetes incidence in these patients. Those with a BMI of more than 30 kg/m² had a statistically significant sixfold increased rate of incident diabetes, compared with patients with a BMI of less than 25 kg/m². Patients with a BMI of 25-30 kg/m² had a significant, nearly twofold increased rate. Patients who received a steroid dose of at least 7.5 mg/day had a statistically significant, twofold increased diabetes incidence, compared with patients who did not receive any steroid treatment.

Dr. Lillegraven said that her study’s findings, added to the earlier findings, support "a potential for tailoring treatment in high-risk individuals." But it is still too early to draw any definite conclusions regarding how this should be carried out in the clinic, she cautioned.

Dr. Lillegraven declared no conflicts of interest relevant to her study. Dr. Solomon declared unpaid consultancies for Pfizer and Novartis. Three other coauthors reported financial relationships with pharmaceutical firms and CORRONA, a database registry for rheumatologic diseases; one is an employee of CORRONA.