EULAR (European League Against Rheumatism): 2013 Congress

MADRID – Patients with systemic sclerosis should undergo annual screening for pulmonary arterial hypertension using a combination of transthoracic echocardiography and pulmonary function tests, an international expert panel said.

These are the first evidence- and consensus-based recommendations for pulmonary arterial hypertension (PAH) screening in patients with systemic sclerosis, and the panel also called for screening patients with mixed or other connective tissue diseases with scleroderma features. "Our hope is that these recommendations will lead to earlier detection of PAH in connective tissue diseases and improve patient outcomes," Dr. Dinesh Khanna said while presenting the screening recommendations at the annual European Congress of Rheumatology.

About 5%-15% of patients with systemic sclerosis develop PAH, and once PAH occurs, up to 30% of patients will die within 3 years, said Dr. Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor.

"Despite having approved drugs available" to treat systemic sclerosis and other scleroderma-spectrum disorder connective tissue diseases, these treatments "have not had a huge impact on survival. The only thing we can offer patients is screening, followed by early diagnosis and treatment," Dr. Khanna said in an interview.

The new recommendations say that patients with a tricuspid regurgitant velocity measured by transthoracic echocardiography greater than 2.8 m/s require assessment for PAH by right heart catheterization. Right heart catheterization is also needed for patients with a tricuspid regurgitant velocity of 2.5-2.8 m/s if they also have signs or symptoms of PAH such as dyspnea, fatigue, chest pain, dizziness, loud pulmonary sound, or peripheral edema. Another echo finding that should trigger right heart catheterization regardless of signs or symptoms or tricuspid regurgitation is right atrial or ventricular enlargement.

The key measures on pulmonary function tests that trigger right heart catheterization is a forced vital capacity (FVC) to diffusion capacity of lungs for carbon monoxide (DLCO) ratio of more than 1.6, or a DLCO of less than 60% if either appears in the setting of PAH signs or symptoms. Alternatively, meeting either of these pulmonary criteria should lead to right heart catheterization regardless of signs and symptoms if the patient’s most recent blood level of N-terminal pro-brain natriuretic peptide (NT-ProBNP) was greater than twice the upper limit of normal.

The panel also said that patients should undergo right heart catheterization regardless of PAH signs and symptoms if they fulfill the screening algorithm developed for the DETECT study (Ann. Rheum. Dis. 2013 May 18 [doi:10.1036/annrheumdis-2013-203301]).

The panel recommended annual transthoracic echo and pulmonary function test screening, or more frequently if a patient shows new signs or symptoms. Measurement of NT-ProBNP should happen at baseline, and then be repeated if new signs or symptoms of PAH appear. They also recommended applying the full DETECT screening algorithm in patients diagnosed with systemic sclerosis or other scleroderma spectrum connective-tissue disease for more than 3 years and a DLCO that is less than 60%. Right heart catheterization is mandatory to definitively diagnose PAH, Dr. Khanna stressed. The panel also said screening is not needed in patients with mixed- or other connective tissue disorders who did not have scleroderma-like features.

In a separate report at the meeting Dr. Khanna and his associates assessed the ability of transthoracic echocardiography and pulmonary function tests to screen patients with PAH. They used data from 69 patients with PAH in two separate reported series that together had 347 patients with systemic sclerosis who underwent assessment for suspected PAH (J. Rheumatol. 2011;38:2172-9 and J. Rheumatol. 2010;37:2290-8).

The new, retrospective analysis showed that combining transthoracic echo and pulmonary-function test screens can have a negative predictive accuracy of 98% for correctly ruling out PAH in patients with systemic sclerosis, reported Dr. Heather Gladue, a rheumatology fellow at the University of Michigan.

The recommendations panel cautioned that its proposals should not substitute for individualized, direct assessment of each patient. The panel also noted that the cost effectiveness of its recommendations had not yet been assessed. In addition to representatives from the University of Michigan, the task force included members from the University of California, Los Angeles; Massachusetts General Hospital, Boston; Stanford (Calif.) University; the University of Zurich; University Hospital in Lille, France; the University of Paris-South; McGill University, Montreal; Johns Hopkins University, Baltimore; and St. Joseph Hospital, Phoenix.

The task force was supported by the Scleroderma Foundation and the Pulmonary Hypertension Association. Dr. Khanna said that he has been a consultant to several drug companies including Actelion, Bayer, Genentech/Roche, Gilead, Merck, and DIGNA. Dr. Gladue said that she had no disclosures.

mzoler@frontlinemedcom.com

Twitter @mitchelzoler

MADRID – Patients with systemic sclerosis should undergo annual screening for pulmonary arterial hypertension using a combination of transthoracic echocardiography and pulmonary function tests, an international expert panel said.

These are the first evidence- and consensus-based recommendations for pulmonary arterial hypertension (PAH) screening in patients with systemic sclerosis, and the panel also called for screening patients with mixed or other connective tissue diseases with scleroderma features. "Our hope is that these recommendations will lead to earlier detection of PAH in connective tissue diseases and improve patient outcomes," Dr. Dinesh Khanna said while presenting the screening recommendations at the annual European Congress of Rheumatology.

About 5%-15% of patients with systemic sclerosis develop PAH, and once PAH occurs, up to 30% of patients will die within 3 years, said Dr. Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor.

"Despite having approved drugs available" to treat systemic sclerosis and other scleroderma-spectrum disorder connective tissue diseases, these treatments "have not had a huge impact on survival. The only thing we can offer patients is screening, followed by early diagnosis and treatment," Dr. Khanna said in an interview.

The new recommendations say that patients with a tricuspid regurgitant velocity measured by transthoracic echocardiography greater than 2.8 m/s require assessment for PAH by right heart catheterization. Right heart catheterization is also needed for patients with a tricuspid regurgitant velocity of 2.5-2.8 m/s if they also have signs or symptoms of PAH such as dyspnea, fatigue, chest pain, dizziness, loud pulmonary sound, or peripheral edema. Another echo finding that should trigger right heart catheterization regardless of signs or symptoms or tricuspid regurgitation is right atrial or ventricular enlargement.

The key measures on pulmonary function tests that trigger right heart catheterization is a forced vital capacity (FVC) to diffusion capacity of lungs for carbon monoxide (DLCO) ratio of more than 1.6, or a DLCO of less than 60% if either appears in the setting of PAH signs or symptoms. Alternatively, meeting either of these pulmonary criteria should lead to right heart catheterization regardless of signs and symptoms if the patient’s most recent blood level of N-terminal pro-brain natriuretic peptide (NT-ProBNP) was greater than twice the upper limit of normal.

The panel also said that patients should undergo right heart catheterization regardless of PAH signs and symptoms if they fulfill the screening algorithm developed for the DETECT study (Ann. Rheum. Dis. 2013 May 18 [doi:10.1036/annrheumdis-2013-203301]).

The panel recommended annual transthoracic echo and pulmonary function test screening, or more frequently if a patient shows new signs or symptoms. Measurement of NT-ProBNP should happen at baseline, and then be repeated if new signs or symptoms of PAH appear. They also recommended applying the full DETECT screening algorithm in patients diagnosed with systemic sclerosis or other scleroderma spectrum connective-tissue disease for more than 3 years and a DLCO that is less than 60%. Right heart catheterization is mandatory to definitively diagnose PAH, Dr. Khanna stressed. The panel also said screening is not needed in patients with mixed- or other connective tissue disorders who did not have scleroderma-like features.

In a separate report at the meeting Dr. Khanna and his associates assessed the ability of transthoracic echocardiography and pulmonary function tests to screen patients with PAH. They used data from 69 patients with PAH in two separate reported series that together had 347 patients with systemic sclerosis who underwent assessment for suspected PAH (J. Rheumatol. 2011;38:2172-9 and J. Rheumatol. 2010;37:2290-8).

The new, retrospective analysis showed that combining transthoracic echo and pulmonary-function test screens can have a negative predictive accuracy of 98% for correctly ruling out PAH in patients with systemic sclerosis, reported Dr. Heather Gladue, a rheumatology fellow at the University of Michigan.

The recommendations panel cautioned that its proposals should not substitute for individualized, direct assessment of each patient. The panel also noted that the cost effectiveness of its recommendations had not yet been assessed. In addition to representatives from the University of Michigan, the task force included members from the University of California, Los Angeles; Massachusetts General Hospital, Boston; Stanford (Calif.) University; the University of Zurich; University Hospital in Lille, France; the University of Paris-South; McGill University, Montreal; Johns Hopkins University, Baltimore; and St. Joseph Hospital, Phoenix.

The task force was supported by the Scleroderma Foundation and the Pulmonary Hypertension Association. Dr. Khanna said that he has been a consultant to several drug companies including Actelion, Bayer, Genentech/Roche, Gilead, Merck, and DIGNA. Dr. Gladue said that she had no disclosures.

mzoler@frontlinemedcom.com

Twitter @mitchelzoler

MADRID – Patients with systemic sclerosis should undergo annual screening for pulmonary arterial hypertension using a combination of transthoracic echocardiography and pulmonary function tests, an international expert panel said.

These are the first evidence- and consensus-based recommendations for pulmonary arterial hypertension (PAH) screening in patients with systemic sclerosis, and the panel also called for screening patients with mixed or other connective tissue diseases with scleroderma features. "Our hope is that these recommendations will lead to earlier detection of PAH in connective tissue diseases and improve patient outcomes," Dr. Dinesh Khanna said while presenting the screening recommendations at the annual European Congress of Rheumatology.

About 5%-15% of patients with systemic sclerosis develop PAH, and once PAH occurs, up to 30% of patients will die within 3 years, said Dr. Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor.

"Despite having approved drugs available" to treat systemic sclerosis and other scleroderma-spectrum disorder connective tissue diseases, these treatments "have not had a huge impact on survival. The only thing we can offer patients is screening, followed by early diagnosis and treatment," Dr. Khanna said in an interview.

The new recommendations say that patients with a tricuspid regurgitant velocity measured by transthoracic echocardiography greater than 2.8 m/s require assessment for PAH by right heart catheterization. Right heart catheterization is also needed for patients with a tricuspid regurgitant velocity of 2.5-2.8 m/s if they also have signs or symptoms of PAH such as dyspnea, fatigue, chest pain, dizziness, loud pulmonary sound, or peripheral edema. Another echo finding that should trigger right heart catheterization regardless of signs or symptoms or tricuspid regurgitation is right atrial or ventricular enlargement.

The key measures on pulmonary function tests that trigger right heart catheterization is a forced vital capacity (FVC) to diffusion capacity of lungs for carbon monoxide (DLCO) ratio of more than 1.6, or a DLCO of less than 60% if either appears in the setting of PAH signs or symptoms. Alternatively, meeting either of these pulmonary criteria should lead to right heart catheterization regardless of signs and symptoms if the patient’s most recent blood level of N-terminal pro-brain natriuretic peptide (NT-ProBNP) was greater than twice the upper limit of normal.

The panel also said that patients should undergo right heart catheterization regardless of PAH signs and symptoms if they fulfill the screening algorithm developed for the DETECT study (Ann. Rheum. Dis. 2013 May 18 [doi:10.1036/annrheumdis-2013-203301]).

The panel recommended annual transthoracic echo and pulmonary function test screening, or more frequently if a patient shows new signs or symptoms. Measurement of NT-ProBNP should happen at baseline, and then be repeated if new signs or symptoms of PAH appear. They also recommended applying the full DETECT screening algorithm in patients diagnosed with systemic sclerosis or other scleroderma spectrum connective-tissue disease for more than 3 years and a DLCO that is less than 60%. Right heart catheterization is mandatory to definitively diagnose PAH, Dr. Khanna stressed. The panel also said screening is not needed in patients with mixed- or other connective tissue disorders who did not have scleroderma-like features.

In a separate report at the meeting Dr. Khanna and his associates assessed the ability of transthoracic echocardiography and pulmonary function tests to screen patients with PAH. They used data from 69 patients with PAH in two separate reported series that together had 347 patients with systemic sclerosis who underwent assessment for suspected PAH (J. Rheumatol. 2011;38:2172-9 and J. Rheumatol. 2010;37:2290-8).

The new, retrospective analysis showed that combining transthoracic echo and pulmonary-function test screens can have a negative predictive accuracy of 98% for correctly ruling out PAH in patients with systemic sclerosis, reported Dr. Heather Gladue, a rheumatology fellow at the University of Michigan.

The recommendations panel cautioned that its proposals should not substitute for individualized, direct assessment of each patient. The panel also noted that the cost effectiveness of its recommendations had not yet been assessed. In addition to representatives from the University of Michigan, the task force included members from the University of California, Los Angeles; Massachusetts General Hospital, Boston; Stanford (Calif.) University; the University of Zurich; University Hospital in Lille, France; the University of Paris-South; McGill University, Montreal; Johns Hopkins University, Baltimore; and St. Joseph Hospital, Phoenix.

The task force was supported by the Scleroderma Foundation and the Pulmonary Hypertension Association. Dr. Khanna said that he has been a consultant to several drug companies including Actelion, Bayer, Genentech/Roche, Gilead, Merck, and DIGNA. Dr. Gladue said that she had no disclosures.

mzoler@frontlinemedcom.com

Twitter @mitchelzoler

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 – The use of a two-step algorithm significantly increased the rate at which pulmonary arterial hypertension was diagnosed in patients with systemic sclerosis in a prospective, observational, cross-sectional study.

The results of the DETECT study, presented at the annual European Congress of Rheumatology, showed that the two-step algorithm had a sensitivity of 96% for correctly identifying the condition, which was higher than the 71% sensitivity obtained using methods recommended currently by the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. The ESC/ERS recommendations are mainly based on consensus rather than robust evidence, and focus on the use of transthoracic echocardiography.

"DETECT is unique because it shows that if you just do an echocardiogram that you miss 29% of people who subsequently have pulmonary arterial hypertension [PAH], whereas if you apply the DETECT algorithm you miss only 4% of the people," Dr. Dinesh Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor, said in an interview.

Dr. Khanna, who was a coinvestigator in the study, added: "PAH is a leading cause of mortality; it has high prevalence [and] it has a median survival of 2 to 3 years. ... You don’t want to miss these patients." Dr. Khanna presented recommendations for annual screening of PAH in systemic sclerosis patients at another session at the meeting.

Although 4% of patients are still being missed, this is a dramatic improvement over current clinical practice, said DETECT investigator Dr. Christopher Denton, who presented the findings of the international, multicenter trial. The study was also recently published online (Ann. Rheum. Dis. 2013 May 18 [doi: 10.1136/annrheumdis-2013-203301]).

"There is a general feeling that patients need to be screened so that diagnoses can be made and licensed therapies can be initiated," said Dr. Denton of the Royal Free Hospital in London. "The goal of the study was to rationalize a large number of potential variables into a small number that could be developed into a risk score," he added, and "ultimately to ensure that the most appropriate patients are referred for diagnostic right heart catheter studies." Right heart catheterization (RHC) remains the only method for confirming a diagnosis of PAH.

A total of 646 adult patients with established scleroderma (greater than 3 years) and reduced diffusing capacity of the lung for carbon monoxide (DLCO less than 60% of predicted) were screened and 466 enrolled in the study. All of them underwent RHC, and 145 (31%) were found to have PAH. This was defined as a mean pulmonary arterial pressure of 25 mm Hg or higher.

Of the 145 patients with PAH, 87 met World Health Organization (WHO) group 1 criteria for mild PAH, and this was the group of interest, as a diagnosis of PAH "had been robustly excluded" by normal methods, Dr. Denton said. This group of patients was compared with the group that did not have PAH (n = 321).

Patients with WHO group 1 PAH were slightly older than patients who did not have PAH (mean ages, 61 and 56 years). The PAH patients also tended to have a longer disease duration (163 vs. 130 months) and had slightly lower DLCO (43% vs. 48% of predicted).

The DETECT investigators examined 112 variables, including demographic and clinical parameters, serum tests, and electro- and echocardiogram results, that they thought might be able to help differentiate patients with PAH from those without it. After expert analysis and various types of statistical modeling, they ended up with eight items that were used to develop the two-step algorithm.

Step 1 of the algorithm involves testing for lung function, expressed as a ratio of the percentage predicted forced vital capacity and DLCO; the presence of current or past telangiectasia; serum anticentromere antibody positivity; serum levels of N-terminal prohormone brain natriuretic peptide (NT-proBNP); serum urate levels; and right axis deviation on an electrocardiogram. Step 2 involves measurement of two echocardiographic parameters: right atrium area and tricuspid regurgitation velocity.

"The aim is to make this a computer-based system," Dr. Denton explained. A trial electronic version of the tool is being tested, which involves the aforementioned clinical variables being entered first to determine if an echocardiogram is warranted, and then determining if the results of the echocardiogram warrant further referral for RHC.

The rates of referral for RHC were higher if the two-step algorithm was used, compared with the use of ESC/ERS guideline-recommended methods (62% and 40%). The specificity of the algorithm was 48%, with positive and negative predictive values of 35% and 98%, respectively. The values for guideline-recommended methods were 69%, 40%, and 89%.

The DETECT algorithm has the potential to revise standards of care in patients with systemic sclerosis. Dr. Denton noted that not only was it a sensitive, noninvasive screening tool, but that it also had the potential to reduce the number of missed diagnoses and to potentially identify PAH earlier in mildly symptomatic patients.

"The reason to use a two-step approach is that this potentially will improve the use of echocardiography as well as the more invasive test of right heart catheterization," he commented. "So we hope that this sort of approach will ultimately improve the approach and the standard of care for systemic sclerosis."

DETECT was an academic-led study funded by Actelion. Dr. Denton has received consulting and speaker fees and/or research funding from, or has been a clinical trial investigator for, several companies including Actelion, Boehringer Ingelheim, and CSL Behring. Dr. Khanna disclosed acting as a consultant for several companies including Actelion, Bayer, and Celgene.

MADRID – The use of a two-step algorithm significantly increased the rate at which pulmonary arterial hypertension was diagnosed in patients with systemic sclerosis in a prospective, observational, cross-sectional study.

The results of the DETECT study, presented at the annual European Congress of Rheumatology, showed that the two-step algorithm had a sensitivity of 96% for correctly identifying the condition, which was higher than the 71% sensitivity obtained using methods recommended currently by the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. The ESC/ERS recommendations are mainly based on consensus rather than robust evidence, and focus on the use of transthoracic echocardiography.

"DETECT is unique because it shows that if you just do an echocardiogram that you miss 29% of people who subsequently have pulmonary arterial hypertension [PAH], whereas if you apply the DETECT algorithm you miss only 4% of the people," Dr. Dinesh Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor, said in an interview.

Dr. Khanna, who was a coinvestigator in the study, added: "PAH is a leading cause of mortality; it has high prevalence [and] it has a median survival of 2 to 3 years. ... You don’t want to miss these patients." Dr. Khanna presented recommendations for annual screening of PAH in systemic sclerosis patients at another session at the meeting.

Although 4% of patients are still being missed, this is a dramatic improvement over current clinical practice, said DETECT investigator Dr. Christopher Denton, who presented the findings of the international, multicenter trial. The study was also recently published online (Ann. Rheum. Dis. 2013 May 18 [doi: 10.1136/annrheumdis-2013-203301]).

"There is a general feeling that patients need to be screened so that diagnoses can be made and licensed therapies can be initiated," said Dr. Denton of the Royal Free Hospital in London. "The goal of the study was to rationalize a large number of potential variables into a small number that could be developed into a risk score," he added, and "ultimately to ensure that the most appropriate patients are referred for diagnostic right heart catheter studies." Right heart catheterization (RHC) remains the only method for confirming a diagnosis of PAH.

A total of 646 adult patients with established scleroderma (greater than 3 years) and reduced diffusing capacity of the lung for carbon monoxide (DLCO less than 60% of predicted) were screened and 466 enrolled in the study. All of them underwent RHC, and 145 (31%) were found to have PAH. This was defined as a mean pulmonary arterial pressure of 25 mm Hg or higher.

Of the 145 patients with PAH, 87 met World Health Organization (WHO) group 1 criteria for mild PAH, and this was the group of interest, as a diagnosis of PAH "had been robustly excluded" by normal methods, Dr. Denton said. This group of patients was compared with the group that did not have PAH (n = 321).

Patients with WHO group 1 PAH were slightly older than patients who did not have PAH (mean ages, 61 and 56 years). The PAH patients also tended to have a longer disease duration (163 vs. 130 months) and had slightly lower DLCO (43% vs. 48% of predicted).

The DETECT investigators examined 112 variables, including demographic and clinical parameters, serum tests, and electro- and echocardiogram results, that they thought might be able to help differentiate patients with PAH from those without it. After expert analysis and various types of statistical modeling, they ended up with eight items that were used to develop the two-step algorithm.

Step 1 of the algorithm involves testing for lung function, expressed as a ratio of the percentage predicted forced vital capacity and DLCO; the presence of current or past telangiectasia; serum anticentromere antibody positivity; serum levels of N-terminal prohormone brain natriuretic peptide (NT-proBNP); serum urate levels; and right axis deviation on an electrocardiogram. Step 2 involves measurement of two echocardiographic parameters: right atrium area and tricuspid regurgitation velocity.

"The aim is to make this a computer-based system," Dr. Denton explained. A trial electronic version of the tool is being tested, which involves the aforementioned clinical variables being entered first to determine if an echocardiogram is warranted, and then determining if the results of the echocardiogram warrant further referral for RHC.

The rates of referral for RHC were higher if the two-step algorithm was used, compared with the use of ESC/ERS guideline-recommended methods (62% and 40%). The specificity of the algorithm was 48%, with positive and negative predictive values of 35% and 98%, respectively. The values for guideline-recommended methods were 69%, 40%, and 89%.

The DETECT algorithm has the potential to revise standards of care in patients with systemic sclerosis. Dr. Denton noted that not only was it a sensitive, noninvasive screening tool, but that it also had the potential to reduce the number of missed diagnoses and to potentially identify PAH earlier in mildly symptomatic patients.

"The reason to use a two-step approach is that this potentially will improve the use of echocardiography as well as the more invasive test of right heart catheterization," he commented. "So we hope that this sort of approach will ultimately improve the approach and the standard of care for systemic sclerosis."

DETECT was an academic-led study funded by Actelion. Dr. Denton has received consulting and speaker fees and/or research funding from, or has been a clinical trial investigator for, several companies including Actelion, Boehringer Ingelheim, and CSL Behring. Dr. Khanna disclosed acting as a consultant for several companies including Actelion, Bayer, and Celgene.

MADRID – The use of a two-step algorithm significantly increased the rate at which pulmonary arterial hypertension was diagnosed in patients with systemic sclerosis in a prospective, observational, cross-sectional study.

The results of the DETECT study, presented at the annual European Congress of Rheumatology, showed that the two-step algorithm had a sensitivity of 96% for correctly identifying the condition, which was higher than the 71% sensitivity obtained using methods recommended currently by the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. The ESC/ERS recommendations are mainly based on consensus rather than robust evidence, and focus on the use of transthoracic echocardiography.

"DETECT is unique because it shows that if you just do an echocardiogram that you miss 29% of people who subsequently have pulmonary arterial hypertension [PAH], whereas if you apply the DETECT algorithm you miss only 4% of the people," Dr. Dinesh Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor, said in an interview.

Dr. Khanna, who was a coinvestigator in the study, added: "PAH is a leading cause of mortality; it has high prevalence [and] it has a median survival of 2 to 3 years. ... You don’t want to miss these patients." Dr. Khanna presented recommendations for annual screening of PAH in systemic sclerosis patients at another session at the meeting.

Although 4% of patients are still being missed, this is a dramatic improvement over current clinical practice, said DETECT investigator Dr. Christopher Denton, who presented the findings of the international, multicenter trial. The study was also recently published online (Ann. Rheum. Dis. 2013 May 18 [doi: 10.1136/annrheumdis-2013-203301]).

"There is a general feeling that patients need to be screened so that diagnoses can be made and licensed therapies can be initiated," said Dr. Denton of the Royal Free Hospital in London. "The goal of the study was to rationalize a large number of potential variables into a small number that could be developed into a risk score," he added, and "ultimately to ensure that the most appropriate patients are referred for diagnostic right heart catheter studies." Right heart catheterization (RHC) remains the only method for confirming a diagnosis of PAH.

A total of 646 adult patients with established scleroderma (greater than 3 years) and reduced diffusing capacity of the lung for carbon monoxide (DLCO less than 60% of predicted) were screened and 466 enrolled in the study. All of them underwent RHC, and 145 (31%) were found to have PAH. This was defined as a mean pulmonary arterial pressure of 25 mm Hg or higher.

Of the 145 patients with PAH, 87 met World Health Organization (WHO) group 1 criteria for mild PAH, and this was the group of interest, as a diagnosis of PAH "had been robustly excluded" by normal methods, Dr. Denton said. This group of patients was compared with the group that did not have PAH (n = 321).

Patients with WHO group 1 PAH were slightly older than patients who did not have PAH (mean ages, 61 and 56 years). The PAH patients also tended to have a longer disease duration (163 vs. 130 months) and had slightly lower DLCO (43% vs. 48% of predicted).

The DETECT investigators examined 112 variables, including demographic and clinical parameters, serum tests, and electro- and echocardiogram results, that they thought might be able to help differentiate patients with PAH from those without it. After expert analysis and various types of statistical modeling, they ended up with eight items that were used to develop the two-step algorithm.

Step 1 of the algorithm involves testing for lung function, expressed as a ratio of the percentage predicted forced vital capacity and DLCO; the presence of current or past telangiectasia; serum anticentromere antibody positivity; serum levels of N-terminal prohormone brain natriuretic peptide (NT-proBNP); serum urate levels; and right axis deviation on an electrocardiogram. Step 2 involves measurement of two echocardiographic parameters: right atrium area and tricuspid regurgitation velocity.

"The aim is to make this a computer-based system," Dr. Denton explained. A trial electronic version of the tool is being tested, which involves the aforementioned clinical variables being entered first to determine if an echocardiogram is warranted, and then determining if the results of the echocardiogram warrant further referral for RHC.

The rates of referral for RHC were higher if the two-step algorithm was used, compared with the use of ESC/ERS guideline-recommended methods (62% and 40%). The specificity of the algorithm was 48%, with positive and negative predictive values of 35% and 98%, respectively. The values for guideline-recommended methods were 69%, 40%, and 89%.

The DETECT algorithm has the potential to revise standards of care in patients with systemic sclerosis. Dr. Denton noted that not only was it a sensitive, noninvasive screening tool, but that it also had the potential to reduce the number of missed diagnoses and to potentially identify PAH earlier in mildly symptomatic patients.

"The reason to use a two-step approach is that this potentially will improve the use of echocardiography as well as the more invasive test of right heart catheterization," he commented. "So we hope that this sort of approach will ultimately improve the approach and the standard of care for systemic sclerosis."

DETECT was an academic-led study funded by Actelion. Dr. Denton has received consulting and speaker fees and/or research funding from, or has been a clinical trial investigator for, several companies including Actelion, Boehringer Ingelheim, and CSL Behring. Dr. Khanna disclosed acting as a consultant for several companies including Actelion, Bayer, and Celgene.

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.

MADRID – A high percentage of patients with early arthritis have inflammation of the small joints that can be detected with MRI but not by physical examination.

Results of a cross-sectional study, presented by Dr. Annemarie Krabben at the annual European Congress of Rheumatology, found that 66% of wrist, 27% of metacarpophalangeal (MCP), and 13% of metatarsophalangeal (MTP) joints that were not clinically swollen showed signs of inflammation on MRI. However, inflammation on MRI was present in 92% of wrists, 86% of MCP, and 29% of MTP joints that were clinically swollen.

©Leiden University Medical Center

"You would expect that inflammation on MRI would be present in the clinically swollen joints, but we also saw inflammation in the non-swollen joints," explained Dr. Krabben of Leiden University Medical Center in the Netherlands.

Furthermore, "when you look at the joints with MRI-detected inflammation, a lot of these didn’t have clinical inflammation," she added.

Clinical joint swelling was absent but signs of bone marrow edema were detected on MRI in 60% of wrist, 53% of MCP, and 78% of MTP joints. If severe MRI-detected edema was considered, joint swelling was absent in 35%, 39%, and 58% of wrist, MCP, and MTP joints, respectively. Joints without clinical swelling showed signs of inflammation on MRI in 61% of wrist, 64% of MCP, and 77% of MTP joints.

The study involved patients with early arthritis who were part of the Leiden Early Arthritis Clinic cohort. This cohort was established in 1993 to detect and treat inflammatory disorders early in the disease state (Rheumatology [Oxford] 2011;50:93-100).

Upon entry into the cohort, patients underwent a physical examination that included 68 tender and 66 swollen joint counts and 1.5 Tesla MRI of the wrist, MCP, and MTP joints. The latter were used to determine the presence and extent of synovitis, bone marrow edema, and tenosynovitis.

In total, 1,790 small joints were examined in 179 patients who had a median duration of symptoms of 15 weeks. Overall, 30% of wrist, 15% of MCP, and 11% of MTP joints were swollen at physical examination and the majority also showed inflammation on MRI.

"There was a lot of subclinical inflammation, especially bone marrow edema, in the nonswollen joints," Dr. Krabben said. Bone marrow edema is linked to erosive disease progression, she observed and suggested that the next step is to see what happens to patients with subclinical inflammation at baseline, and whether this will eventually progress to erosive disease.

The study was supported by the Dutch Arthritis Foundation (Reumafonds), the Netherlands Organization for Health Research and Development, and the Center for Translational Molecular Medicine. Dr. Krabben has received research funding from Reumafonds.

MADRID – A high percentage of patients with early arthritis have inflammation of the small joints that can be detected with MRI but not by physical examination.

Results of a cross-sectional study, presented by Dr. Annemarie Krabben at the annual European Congress of Rheumatology, found that 66% of wrist, 27% of metacarpophalangeal (MCP), and 13% of metatarsophalangeal (MTP) joints that were not clinically swollen showed signs of inflammation on MRI. However, inflammation on MRI was present in 92% of wrists, 86% of MCP, and 29% of MTP joints that were clinically swollen.

©Leiden University Medical Center

"You would expect that inflammation on MRI would be present in the clinically swollen joints, but we also saw inflammation in the non-swollen joints," explained Dr. Krabben of Leiden University Medical Center in the Netherlands.

Furthermore, "when you look at the joints with MRI-detected inflammation, a lot of these didn’t have clinical inflammation," she added.

Clinical joint swelling was absent but signs of bone marrow edema were detected on MRI in 60% of wrist, 53% of MCP, and 78% of MTP joints. If severe MRI-detected edema was considered, joint swelling was absent in 35%, 39%, and 58% of wrist, MCP, and MTP joints, respectively. Joints without clinical swelling showed signs of inflammation on MRI in 61% of wrist, 64% of MCP, and 77% of MTP joints.

The study involved patients with early arthritis who were part of the Leiden Early Arthritis Clinic cohort. This cohort was established in 1993 to detect and treat inflammatory disorders early in the disease state (Rheumatology [Oxford] 2011;50:93-100).

Upon entry into the cohort, patients underwent a physical examination that included 68 tender and 66 swollen joint counts and 1.5 Tesla MRI of the wrist, MCP, and MTP joints. The latter were used to determine the presence and extent of synovitis, bone marrow edema, and tenosynovitis.

In total, 1,790 small joints were examined in 179 patients who had a median duration of symptoms of 15 weeks. Overall, 30% of wrist, 15% of MCP, and 11% of MTP joints were swollen at physical examination and the majority also showed inflammation on MRI.

"There was a lot of subclinical inflammation, especially bone marrow edema, in the nonswollen joints," Dr. Krabben said. Bone marrow edema is linked to erosive disease progression, she observed and suggested that the next step is to see what happens to patients with subclinical inflammation at baseline, and whether this will eventually progress to erosive disease.

The study was supported by the Dutch Arthritis Foundation (Reumafonds), the Netherlands Organization for Health Research and Development, and the Center for Translational Molecular Medicine. Dr. Krabben has received research funding from Reumafonds.

MADRID – A high percentage of patients with early arthritis have inflammation of the small joints that can be detected with MRI but not by physical examination.

Results of a cross-sectional study, presented by Dr. Annemarie Krabben at the annual European Congress of Rheumatology, found that 66% of wrist, 27% of metacarpophalangeal (MCP), and 13% of metatarsophalangeal (MTP) joints that were not clinically swollen showed signs of inflammation on MRI. However, inflammation on MRI was present in 92% of wrists, 86% of MCP, and 29% of MTP joints that were clinically swollen.

©Leiden University Medical Center

"You would expect that inflammation on MRI would be present in the clinically swollen joints, but we also saw inflammation in the non-swollen joints," explained Dr. Krabben of Leiden University Medical Center in the Netherlands.

Furthermore, "when you look at the joints with MRI-detected inflammation, a lot of these didn’t have clinical inflammation," she added.

Clinical joint swelling was absent but signs of bone marrow edema were detected on MRI in 60% of wrist, 53% of MCP, and 78% of MTP joints. If severe MRI-detected edema was considered, joint swelling was absent in 35%, 39%, and 58% of wrist, MCP, and MTP joints, respectively. Joints without clinical swelling showed signs of inflammation on MRI in 61% of wrist, 64% of MCP, and 77% of MTP joints.

The study involved patients with early arthritis who were part of the Leiden Early Arthritis Clinic cohort. This cohort was established in 1993 to detect and treat inflammatory disorders early in the disease state (Rheumatology [Oxford] 2011;50:93-100).

Upon entry into the cohort, patients underwent a physical examination that included 68 tender and 66 swollen joint counts and 1.5 Tesla MRI of the wrist, MCP, and MTP joints. The latter were used to determine the presence and extent of synovitis, bone marrow edema, and tenosynovitis.

In total, 1,790 small joints were examined in 179 patients who had a median duration of symptoms of 15 weeks. Overall, 30% of wrist, 15% of MCP, and 11% of MTP joints were swollen at physical examination and the majority also showed inflammation on MRI.

"There was a lot of subclinical inflammation, especially bone marrow edema, in the nonswollen joints," Dr. Krabben said. Bone marrow edema is linked to erosive disease progression, she observed and suggested that the next step is to see what happens to patients with subclinical inflammation at baseline, and whether this will eventually progress to erosive disease.

The study was supported by the Dutch Arthritis Foundation (Reumafonds), the Netherlands Organization for Health Research and Development, and the Center for Translational Molecular Medicine. Dr. Krabben has received research funding from Reumafonds.

Symptomatic hand osteoarthritis is associated with a significant increase in the risk of coronary heart disease events, although the association was not significant for asymptomatic hand osteoarthritis, according to results from a study presented at the annual European Congress of Rheumatology.

A population-based cohort study of 1,348 participants from the Framingham Heart Study found more than double the incidence of coronary heart disease among individuals with symptomatic hand OA, compared with those without hand OA (hazard ratio, 2.26; 95% confidence interval, 1.22-4.18), Dr. Ida K. Haugen reported.

The study defined symptomatic hand OA as one or more hand joints with Kellgren-Lawrence grade of 2 or above and pain in the same joint. The definition excluded individuals with rheumatoid arthritis (RA).

The association persisted even after adjustment for lower limb pain (HR, 2.00; 95% CI, 0.96-4.15), to account for the physical inactivity potentially associated with OA in lower limb joints, according to Dr. Haugen from Diakonhjemmet Hospital in Oslo, and her associates.

However, individuals with radiographic but not symptomatic hand OA showed a nonsignificant increase in the risk of coronary heart disease (HR, 1.60; 95% CI, 0.96-2.66).

The study set out to examine a possible association between hand OA and cardiovascular disease, based on the premise that hand OA is especially likely to be related to metabolic rather than mechanical causes.

"We hypothesized that the association between hand OA and coronary heart disease could be mediated through metabolic factors, such as hyperlipidemia and diabetes, or a more sedate lifestyle due to generalized OA," Dr. Haugen said in an interview.

"Radiographic hand OA is very prevalent in the general population, and only a proportion of those with radiographic hand OA may experience symptoms," she said. "We believe that symptomatic hand OA represents more severe hand OA and, further, the association between hand OA and coronary heart disease may be mediated through factors associated with pain, such as synovitis."

Synovitis has been shown in other diseases such as RA to increase the risk of cardiovascular disease due to the development of atherosclerosis, Dr. Haugen said.

The study failed to find any significant associations between hand OA – either symptomatic or radiographic only – and cardiovascular events, overall mortality, heart failure, and atherothrombotic stroke.

"[W]e hypothesize that the varying associations may be due to different risk factors for coronary heart disease versus cerebrovascular disease and congestive heart failure; for example, hypertension seems to be more important for cerebrovascular disease than for coronary heart disease," Dr. Haugen said.

While further research is needed to explore the mechanisms of the association, Dr. Haugen suggested that clinicians note that patients with hand OA may be at greater risk of coronary heart disease, and preventive strategies may therefore be of greater importance in this group.

Dr. Haugen reported having no relevant financial disclosures.

Symptomatic hand osteoarthritis is associated with a significant increase in the risk of coronary heart disease events, although the association was not significant for asymptomatic hand osteoarthritis, according to results from a study presented at the annual European Congress of Rheumatology.

A population-based cohort study of 1,348 participants from the Framingham Heart Study found more than double the incidence of coronary heart disease among individuals with symptomatic hand OA, compared with those without hand OA (hazard ratio, 2.26; 95% confidence interval, 1.22-4.18), Dr. Ida K. Haugen reported.

The study defined symptomatic hand OA as one or more hand joints with Kellgren-Lawrence grade of 2 or above and pain in the same joint. The definition excluded individuals with rheumatoid arthritis (RA).

The association persisted even after adjustment for lower limb pain (HR, 2.00; 95% CI, 0.96-4.15), to account for the physical inactivity potentially associated with OA in lower limb joints, according to Dr. Haugen from Diakonhjemmet Hospital in Oslo, and her associates.

However, individuals with radiographic but not symptomatic hand OA showed a nonsignificant increase in the risk of coronary heart disease (HR, 1.60; 95% CI, 0.96-2.66).

The study set out to examine a possible association between hand OA and cardiovascular disease, based on the premise that hand OA is especially likely to be related to metabolic rather than mechanical causes.

"We hypothesized that the association between hand OA and coronary heart disease could be mediated through metabolic factors, such as hyperlipidemia and diabetes, or a more sedate lifestyle due to generalized OA," Dr. Haugen said in an interview.

"Radiographic hand OA is very prevalent in the general population, and only a proportion of those with radiographic hand OA may experience symptoms," she said. "We believe that symptomatic hand OA represents more severe hand OA and, further, the association between hand OA and coronary heart disease may be mediated through factors associated with pain, such as synovitis."

Synovitis has been shown in other diseases such as RA to increase the risk of cardiovascular disease due to the development of atherosclerosis, Dr. Haugen said.

The study failed to find any significant associations between hand OA – either symptomatic or radiographic only – and cardiovascular events, overall mortality, heart failure, and atherothrombotic stroke.

"[W]e hypothesize that the varying associations may be due to different risk factors for coronary heart disease versus cerebrovascular disease and congestive heart failure; for example, hypertension seems to be more important for cerebrovascular disease than for coronary heart disease," Dr. Haugen said.

While further research is needed to explore the mechanisms of the association, Dr. Haugen suggested that clinicians note that patients with hand OA may be at greater risk of coronary heart disease, and preventive strategies may therefore be of greater importance in this group.

Dr. Haugen reported having no relevant financial disclosures.

Symptomatic hand osteoarthritis is associated with a significant increase in the risk of coronary heart disease events, although the association was not significant for asymptomatic hand osteoarthritis, according to results from a study presented at the annual European Congress of Rheumatology.

A population-based cohort study of 1,348 participants from the Framingham Heart Study found more than double the incidence of coronary heart disease among individuals with symptomatic hand OA, compared with those without hand OA (hazard ratio, 2.26; 95% confidence interval, 1.22-4.18), Dr. Ida K. Haugen reported.

The study defined symptomatic hand OA as one or more hand joints with Kellgren-Lawrence grade of 2 or above and pain in the same joint. The definition excluded individuals with rheumatoid arthritis (RA).

The association persisted even after adjustment for lower limb pain (HR, 2.00; 95% CI, 0.96-4.15), to account for the physical inactivity potentially associated with OA in lower limb joints, according to Dr. Haugen from Diakonhjemmet Hospital in Oslo, and her associates.

However, individuals with radiographic but not symptomatic hand OA showed a nonsignificant increase in the risk of coronary heart disease (HR, 1.60; 95% CI, 0.96-2.66).

The study set out to examine a possible association between hand OA and cardiovascular disease, based on the premise that hand OA is especially likely to be related to metabolic rather than mechanical causes.

"We hypothesized that the association between hand OA and coronary heart disease could be mediated through metabolic factors, such as hyperlipidemia and diabetes, or a more sedate lifestyle due to generalized OA," Dr. Haugen said in an interview.

"Radiographic hand OA is very prevalent in the general population, and only a proportion of those with radiographic hand OA may experience symptoms," she said. "We believe that symptomatic hand OA represents more severe hand OA and, further, the association between hand OA and coronary heart disease may be mediated through factors associated with pain, such as synovitis."

Synovitis has been shown in other diseases such as RA to increase the risk of cardiovascular disease due to the development of atherosclerosis, Dr. Haugen said.

The study failed to find any significant associations between hand OA – either symptomatic or radiographic only – and cardiovascular events, overall mortality, heart failure, and atherothrombotic stroke.

"[W]e hypothesize that the varying associations may be due to different risk factors for coronary heart disease versus cerebrovascular disease and congestive heart failure; for example, hypertension seems to be more important for cerebrovascular disease than for coronary heart disease," Dr. Haugen said.

While further research is needed to explore the mechanisms of the association, Dr. Haugen suggested that clinicians note that patients with hand OA may be at greater risk of coronary heart disease, and preventive strategies may therefore be of greater importance in this group.

Dr. Haugen reported having no relevant financial disclosures.