EULAR (European League Against Rheumatism): 2012 Congress

BERLIN– Rheumatoid arthritis patients face a moderately elevated risk of venous thromboembolism that continues unabated for many years, according to findings from two large studies presented at the European Congress of Rheumatology.

Dr. Seoyoung C. Kim offered a retrospective cohort study involving 22,143 patients with rheumatoid arthritis (RA) and 88,572 age- and sex-matched controls. None of the subjects had a baseline history of malignancy or venous thromboembolism (VTE). The data came from a large U.S. commercial insurance plan.

During a mean follow-up of 2 years (starting when the RA patients received their first prescription for a disease-modifying antirheumatic drug), deep vein thrombosis or pulmonary embolism occurred in 1.2% of RA patients and 0.5% of controls. The incidence among RA patients was 6.1 cases per 1,000 person-years, a rate 2.4-fold greater than in controls. The pulmonary embolism rate was 2.7 times higher than in controls, whereas the deep vein thrombosis rate was 2.2-fold higher, according to Dr. Kim of Brigham and Women’s Hospital, Boston, where she is a rheumatologist.

After adjustment for known risk factors for VTE, including surgery, hospitalization, and cardiovascular disease, the VTE risk associated with having RA remained moderately elevated, with a 40% increase compared with controls.

The mechanism underlying this increased risk is believed to hinge upon the systemic inflammation that is a central feature of RA. This inflammation is thought to predispose to thrombus formation, up-regulation of procoagulants, down-regulation of anticoagulants, and suppression of fibrinolysis, Dr. Kim noted.

Dr. Marie Holmqvist presented a prospective population-based cohort study including 8,077 patients who were newly diagnosed with RA during 1997-2009, as well as 203,329 controls.

In all, 84 RA patients were diagnosed with a pulmonary embolism during 43,178 person-years of prospective follow-up. That translated to an incidence of 1.9 cases per 1,000 person-years, compared with 1.1 cases per 1,000 person-years among controls.

The increased risk of pulmonary embolism was evident 1 year after diagnosis of RA and remained unchanged thereafter. In the period 1-4 years after diagnosis of RA, the RA group had a 1.8-fold greater risk of pulmonary embolism than did controls drawn from the general population. During years 5-9, the risk was increased 2.0-fold, and in years 10-15 the risk of pulmonary embolism in RA patients was 1.9-fold greater than in controls, although only a small number of subjects were followed that long.

Control subjects who were hospitalized for any reason had a 5.4-fold increased risk of pulmonary embolism for the next year, compared with nonhospitalized controls. The risk of pulmonary embolism in hospitalized RA patients was elevated for the next year to the same extent as in hospitalized controls. In other words, having RA didn’t pile on additional risk beyond hospitalization itself, according to Dr. Holmqvist of the Karolinska Institute, Stockholm.

Dr. Holmqvist and Dr. Kim reported having no financial conflicts. Neither study had commercial sponsorship.

BERLIN– Rheumatoid arthritis patients face a moderately elevated risk of venous thromboembolism that continues unabated for many years, according to findings from two large studies presented at the European Congress of Rheumatology.

Dr. Seoyoung C. Kim offered a retrospective cohort study involving 22,143 patients with rheumatoid arthritis (RA) and 88,572 age- and sex-matched controls. None of the subjects had a baseline history of malignancy or venous thromboembolism (VTE). The data came from a large U.S. commercial insurance plan.

During a mean follow-up of 2 years (starting when the RA patients received their first prescription for a disease-modifying antirheumatic drug), deep vein thrombosis or pulmonary embolism occurred in 1.2% of RA patients and 0.5% of controls. The incidence among RA patients was 6.1 cases per 1,000 person-years, a rate 2.4-fold greater than in controls. The pulmonary embolism rate was 2.7 times higher than in controls, whereas the deep vein thrombosis rate was 2.2-fold higher, according to Dr. Kim of Brigham and Women’s Hospital, Boston, where she is a rheumatologist.

After adjustment for known risk factors for VTE, including surgery, hospitalization, and cardiovascular disease, the VTE risk associated with having RA remained moderately elevated, with a 40% increase compared with controls.

The mechanism underlying this increased risk is believed to hinge upon the systemic inflammation that is a central feature of RA. This inflammation is thought to predispose to thrombus formation, up-regulation of procoagulants, down-regulation of anticoagulants, and suppression of fibrinolysis, Dr. Kim noted.

Dr. Marie Holmqvist presented a prospective population-based cohort study including 8,077 patients who were newly diagnosed with RA during 1997-2009, as well as 203,329 controls.

In all, 84 RA patients were diagnosed with a pulmonary embolism during 43,178 person-years of prospective follow-up. That translated to an incidence of 1.9 cases per 1,000 person-years, compared with 1.1 cases per 1,000 person-years among controls.

The increased risk of pulmonary embolism was evident 1 year after diagnosis of RA and remained unchanged thereafter. In the period 1-4 years after diagnosis of RA, the RA group had a 1.8-fold greater risk of pulmonary embolism than did controls drawn from the general population. During years 5-9, the risk was increased 2.0-fold, and in years 10-15 the risk of pulmonary embolism in RA patients was 1.9-fold greater than in controls, although only a small number of subjects were followed that long.

Control subjects who were hospitalized for any reason had a 5.4-fold increased risk of pulmonary embolism for the next year, compared with nonhospitalized controls. The risk of pulmonary embolism in hospitalized RA patients was elevated for the next year to the same extent as in hospitalized controls. In other words, having RA didn’t pile on additional risk beyond hospitalization itself, according to Dr. Holmqvist of the Karolinska Institute, Stockholm.

Dr. Holmqvist and Dr. Kim reported having no financial conflicts. Neither study had commercial sponsorship.

BERLIN– Rheumatoid arthritis patients face a moderately elevated risk of venous thromboembolism that continues unabated for many years, according to findings from two large studies presented at the European Congress of Rheumatology.

Dr. Seoyoung C. Kim offered a retrospective cohort study involving 22,143 patients with rheumatoid arthritis (RA) and 88,572 age- and sex-matched controls. None of the subjects had a baseline history of malignancy or venous thromboembolism (VTE). The data came from a large U.S. commercial insurance plan.

During a mean follow-up of 2 years (starting when the RA patients received their first prescription for a disease-modifying antirheumatic drug), deep vein thrombosis or pulmonary embolism occurred in 1.2% of RA patients and 0.5% of controls. The incidence among RA patients was 6.1 cases per 1,000 person-years, a rate 2.4-fold greater than in controls. The pulmonary embolism rate was 2.7 times higher than in controls, whereas the deep vein thrombosis rate was 2.2-fold higher, according to Dr. Kim of Brigham and Women’s Hospital, Boston, where she is a rheumatologist.

After adjustment for known risk factors for VTE, including surgery, hospitalization, and cardiovascular disease, the VTE risk associated with having RA remained moderately elevated, with a 40% increase compared with controls.

The mechanism underlying this increased risk is believed to hinge upon the systemic inflammation that is a central feature of RA. This inflammation is thought to predispose to thrombus formation, up-regulation of procoagulants, down-regulation of anticoagulants, and suppression of fibrinolysis, Dr. Kim noted.

Dr. Marie Holmqvist presented a prospective population-based cohort study including 8,077 patients who were newly diagnosed with RA during 1997-2009, as well as 203,329 controls.

In all, 84 RA patients were diagnosed with a pulmonary embolism during 43,178 person-years of prospective follow-up. That translated to an incidence of 1.9 cases per 1,000 person-years, compared with 1.1 cases per 1,000 person-years among controls.

The increased risk of pulmonary embolism was evident 1 year after diagnosis of RA and remained unchanged thereafter. In the period 1-4 years after diagnosis of RA, the RA group had a 1.8-fold greater risk of pulmonary embolism than did controls drawn from the general population. During years 5-9, the risk was increased 2.0-fold, and in years 10-15 the risk of pulmonary embolism in RA patients was 1.9-fold greater than in controls, although only a small number of subjects were followed that long.

Control subjects who were hospitalized for any reason had a 5.4-fold increased risk of pulmonary embolism for the next year, compared with nonhospitalized controls. The risk of pulmonary embolism in hospitalized RA patients was elevated for the next year to the same extent as in hospitalized controls. In other words, having RA didn’t pile on additional risk beyond hospitalization itself, according to Dr. Holmqvist of the Karolinska Institute, Stockholm.

Dr. Holmqvist and Dr. Kim reported having no financial conflicts. Neither study had commercial sponsorship.

BERLIN – Tocilizumab monotherapy worked substantially better than adalimumab monotherapy in a head-to-head randomized trial of 326 rheumatoid arthritis patients, suggesting that the newer drug tocilizumab has superior efficacy compared with drugs that block tumor necrosis factor, at least when methotrexate isn’t coadministered.

After 24 weeks of treatment, tocilizumab monotherapy produced remission of rheumatoid arthritis (RA) in 40% of patients, based on their disease activity score in 28 joints (DAS28), compared with an 11% remission rate in patients on adalimumab monotherapy, a significant difference, Dr. Cem Gabay reported at the annual European Congress of Rheumatology.

This is the first direct RA comparison of representatives of these two drug classes, both of which block cytokines, said Dr. Gabay, professor of pathology and immunology at the University of Geneva. Both tocilizumab (Actemra) and adalimumab (Humira) have Food and Drug Administration labeling for the treatment of RA.

"Anti-TNF [tumor necrosis factor] drugs remain the first biologic drugs to try, based on EULAR recommendations, but we showed that if a patient is on monotherapy, tocilizumab might be the better choice," Dr. Gabay said in an interview.

"If a patient is on methotrexate and tolerates methotrexate, there is no reason to stop," and those patients should continue to get a TNF inhibitor. "But many patients don’t tolerate methotrexate, and in these patients tocilizumab may be the choice for a biologic as monotherapy." About a third of RA patients who receive a biologic drug get it as monotherapy and are not on concomitant therapy with a synthetic, disease-modifying antirheumatic drug (DMARD) such as methotrexate, usually because they don’t tolerate those drugs or because their preference is to avoid them.

"This needs to be confirmed by other studies, but according to these new data, when patients cannot tolerate a synthetic DMARD they will do better on tocilizumab than with an anti-TNF drug," Dr. Gabay said. "But for the majority of patients [who are on synthetic DMARD treatment], an anti-TNF drug remains the first line. They have been around for 10 years, and are much more studied than tocilizumab."

The finding is important for RA practice because "we don’t have many head-to-head studies of biologics," commented Dr. Xavier Mariette, professor and head of rheumatology at Bicetre Hospital in Paris. But he questioned the fairness of using adalimumab as the study’s representative anti-TNF drug, noting its documented immunogenicity, especially when used in monotherapy. "Other monotherapy would have been more appropriate," he said.

In response, Dr. Gabay highlighted the separation in average DAS28 scores that occurred after 8 weeks of treatment between the two study arms, the point when patients on tocilizumab began to have significantly lower scores than the adalimumab patients. The difference seems to occur too soon to result from an immune reaction to adalimumab, Dr. Gabay said.

The ADACTA trial enrolled 326 adults with RA at 82 centers in 15 countries including the United States. Enrollment criteria included having RA for at least 6 months and a DAS28 score of more than 5.1. All patients were naive for biologic drugs, but they could have had prior or current treatment with methotrexate or other synthetic DMARDs. All DMARDs were withdrawn at least 2 weeks before the study began. The patients had a mean age of 53 years, 80% were women, their average RA duration was more than 6 years, they had a history with average of two DMARDs, slightly more than half were on an oral steroid, and their mean DAS28 score was about 6.7.

The researchers randomized patients to receive 8 mg/kg tocilizumab intravenously every 4 weeks, or 40 mg of subcutaneous adalimumab every 2 weeks. Patients also received placebo treatments to blind everyone to the active-drug assignments.

For the study’s primary end point, average change in DAS28 score from baseline to 24 weeks on treatment, the reductions averaged 1.8 points in the adalimumab group and 3.3 points in the tocilizumab group, a significant difference. Low disease activity, defined as a DAS28 score of 3.2 or less, occurred in 20% of the adalimumab patients and in 52% of those on tocilizumab, also a significant difference. A 20% improvement by the criteria of the American College of Rheumatology (ACR20) occurred in 49% of the adalimumab patients, and their ACR50 and ACR70 rates were 28% and 18%, respectively. In the tocilizumab patients, the ACR20/50/70 rates were 65%, 47%, and 33%, respectively.

The rates of serious adverse events, infections, and serious infections were all similar in the two treatment arms. Infections occurred in 42% of the adalimumab patients and in 48% of those on tocilizumab, and serious infections occurred in 3% of both groups. Serious adverse events occurred in 10% of the adalimumab patients and in 12% of those on tocilizumab. Patients on tocilizumab had moderately higher rates of elevated liver enzymes. The tocilizumab patients had a 31% rate of enzymes elevated from above the upper limit of normal (ULN) to 2.5-fold the ULN, compared with 25% of the adalimumab patients; and liver enzyme elevations of 2.6-5.0 times the ULN occurred in 6% of the tocilizumab patients and in 2% of those on adalimumab. Tocilizumab showed "no new or unexpected adverse effects," Dr. Gabay said.

The study was sponsored by Roche, the company that markets tocilizumab. Dr. Gabay reported receiving research support from and being a consultant to Roche and several other drug companies. Dr. Mariette reported receiving research support from Roche and several other drug companies.

BERLIN – Tocilizumab monotherapy worked substantially better than adalimumab monotherapy in a head-to-head randomized trial of 326 rheumatoid arthritis patients, suggesting that the newer drug tocilizumab has superior efficacy compared with drugs that block tumor necrosis factor, at least when methotrexate isn’t coadministered.

After 24 weeks of treatment, tocilizumab monotherapy produced remission of rheumatoid arthritis (RA) in 40% of patients, based on their disease activity score in 28 joints (DAS28), compared with an 11% remission rate in patients on adalimumab monotherapy, a significant difference, Dr. Cem Gabay reported at the annual European Congress of Rheumatology.

This is the first direct RA comparison of representatives of these two drug classes, both of which block cytokines, said Dr. Gabay, professor of pathology and immunology at the University of Geneva. Both tocilizumab (Actemra) and adalimumab (Humira) have Food and Drug Administration labeling for the treatment of RA.

"Anti-TNF [tumor necrosis factor] drugs remain the first biologic drugs to try, based on EULAR recommendations, but we showed that if a patient is on monotherapy, tocilizumab might be the better choice," Dr. Gabay said in an interview.

"If a patient is on methotrexate and tolerates methotrexate, there is no reason to stop," and those patients should continue to get a TNF inhibitor. "But many patients don’t tolerate methotrexate, and in these patients tocilizumab may be the choice for a biologic as monotherapy." About a third of RA patients who receive a biologic drug get it as monotherapy and are not on concomitant therapy with a synthetic, disease-modifying antirheumatic drug (DMARD) such as methotrexate, usually because they don’t tolerate those drugs or because their preference is to avoid them.

"This needs to be confirmed by other studies, but according to these new data, when patients cannot tolerate a synthetic DMARD they will do better on tocilizumab than with an anti-TNF drug," Dr. Gabay said. "But for the majority of patients [who are on synthetic DMARD treatment], an anti-TNF drug remains the first line. They have been around for 10 years, and are much more studied than tocilizumab."

The finding is important for RA practice because "we don’t have many head-to-head studies of biologics," commented Dr. Xavier Mariette, professor and head of rheumatology at Bicetre Hospital in Paris. But he questioned the fairness of using adalimumab as the study’s representative anti-TNF drug, noting its documented immunogenicity, especially when used in monotherapy. "Other monotherapy would have been more appropriate," he said.

In response, Dr. Gabay highlighted the separation in average DAS28 scores that occurred after 8 weeks of treatment between the two study arms, the point when patients on tocilizumab began to have significantly lower scores than the adalimumab patients. The difference seems to occur too soon to result from an immune reaction to adalimumab, Dr. Gabay said.

The ADACTA trial enrolled 326 adults with RA at 82 centers in 15 countries including the United States. Enrollment criteria included having RA for at least 6 months and a DAS28 score of more than 5.1. All patients were naive for biologic drugs, but they could have had prior or current treatment with methotrexate or other synthetic DMARDs. All DMARDs were withdrawn at least 2 weeks before the study began. The patients had a mean age of 53 years, 80% were women, their average RA duration was more than 6 years, they had a history with average of two DMARDs, slightly more than half were on an oral steroid, and their mean DAS28 score was about 6.7.

The researchers randomized patients to receive 8 mg/kg tocilizumab intravenously every 4 weeks, or 40 mg of subcutaneous adalimumab every 2 weeks. Patients also received placebo treatments to blind everyone to the active-drug assignments.

For the study’s primary end point, average change in DAS28 score from baseline to 24 weeks on treatment, the reductions averaged 1.8 points in the adalimumab group and 3.3 points in the tocilizumab group, a significant difference. Low disease activity, defined as a DAS28 score of 3.2 or less, occurred in 20% of the adalimumab patients and in 52% of those on tocilizumab, also a significant difference. A 20% improvement by the criteria of the American College of Rheumatology (ACR20) occurred in 49% of the adalimumab patients, and their ACR50 and ACR70 rates were 28% and 18%, respectively. In the tocilizumab patients, the ACR20/50/70 rates were 65%, 47%, and 33%, respectively.

The rates of serious adverse events, infections, and serious infections were all similar in the two treatment arms. Infections occurred in 42% of the adalimumab patients and in 48% of those on tocilizumab, and serious infections occurred in 3% of both groups. Serious adverse events occurred in 10% of the adalimumab patients and in 12% of those on tocilizumab. Patients on tocilizumab had moderately higher rates of elevated liver enzymes. The tocilizumab patients had a 31% rate of enzymes elevated from above the upper limit of normal (ULN) to 2.5-fold the ULN, compared with 25% of the adalimumab patients; and liver enzyme elevations of 2.6-5.0 times the ULN occurred in 6% of the tocilizumab patients and in 2% of those on adalimumab. Tocilizumab showed "no new or unexpected adverse effects," Dr. Gabay said.

The study was sponsored by Roche, the company that markets tocilizumab. Dr. Gabay reported receiving research support from and being a consultant to Roche and several other drug companies. Dr. Mariette reported receiving research support from Roche and several other drug companies.

BERLIN – Tocilizumab monotherapy worked substantially better than adalimumab monotherapy in a head-to-head randomized trial of 326 rheumatoid arthritis patients, suggesting that the newer drug tocilizumab has superior efficacy compared with drugs that block tumor necrosis factor, at least when methotrexate isn’t coadministered.

After 24 weeks of treatment, tocilizumab monotherapy produced remission of rheumatoid arthritis (RA) in 40% of patients, based on their disease activity score in 28 joints (DAS28), compared with an 11% remission rate in patients on adalimumab monotherapy, a significant difference, Dr. Cem Gabay reported at the annual European Congress of Rheumatology.

This is the first direct RA comparison of representatives of these two drug classes, both of which block cytokines, said Dr. Gabay, professor of pathology and immunology at the University of Geneva. Both tocilizumab (Actemra) and adalimumab (Humira) have Food and Drug Administration labeling for the treatment of RA.

"Anti-TNF [tumor necrosis factor] drugs remain the first biologic drugs to try, based on EULAR recommendations, but we showed that if a patient is on monotherapy, tocilizumab might be the better choice," Dr. Gabay said in an interview.

"If a patient is on methotrexate and tolerates methotrexate, there is no reason to stop," and those patients should continue to get a TNF inhibitor. "But many patients don’t tolerate methotrexate, and in these patients tocilizumab may be the choice for a biologic as monotherapy." About a third of RA patients who receive a biologic drug get it as monotherapy and are not on concomitant therapy with a synthetic, disease-modifying antirheumatic drug (DMARD) such as methotrexate, usually because they don’t tolerate those drugs or because their preference is to avoid them.

"This needs to be confirmed by other studies, but according to these new data, when patients cannot tolerate a synthetic DMARD they will do better on tocilizumab than with an anti-TNF drug," Dr. Gabay said. "But for the majority of patients [who are on synthetic DMARD treatment], an anti-TNF drug remains the first line. They have been around for 10 years, and are much more studied than tocilizumab."

The finding is important for RA practice because "we don’t have many head-to-head studies of biologics," commented Dr. Xavier Mariette, professor and head of rheumatology at Bicetre Hospital in Paris. But he questioned the fairness of using adalimumab as the study’s representative anti-TNF drug, noting its documented immunogenicity, especially when used in monotherapy. "Other monotherapy would have been more appropriate," he said.

In response, Dr. Gabay highlighted the separation in average DAS28 scores that occurred after 8 weeks of treatment between the two study arms, the point when patients on tocilizumab began to have significantly lower scores than the adalimumab patients. The difference seems to occur too soon to result from an immune reaction to adalimumab, Dr. Gabay said.

The ADACTA trial enrolled 326 adults with RA at 82 centers in 15 countries including the United States. Enrollment criteria included having RA for at least 6 months and a DAS28 score of more than 5.1. All patients were naive for biologic drugs, but they could have had prior or current treatment with methotrexate or other synthetic DMARDs. All DMARDs were withdrawn at least 2 weeks before the study began. The patients had a mean age of 53 years, 80% were women, their average RA duration was more than 6 years, they had a history with average of two DMARDs, slightly more than half were on an oral steroid, and their mean DAS28 score was about 6.7.

The researchers randomized patients to receive 8 mg/kg tocilizumab intravenously every 4 weeks, or 40 mg of subcutaneous adalimumab every 2 weeks. Patients also received placebo treatments to blind everyone to the active-drug assignments.

For the study’s primary end point, average change in DAS28 score from baseline to 24 weeks on treatment, the reductions averaged 1.8 points in the adalimumab group and 3.3 points in the tocilizumab group, a significant difference. Low disease activity, defined as a DAS28 score of 3.2 or less, occurred in 20% of the adalimumab patients and in 52% of those on tocilizumab, also a significant difference. A 20% improvement by the criteria of the American College of Rheumatology (ACR20) occurred in 49% of the adalimumab patients, and their ACR50 and ACR70 rates were 28% and 18%, respectively. In the tocilizumab patients, the ACR20/50/70 rates were 65%, 47%, and 33%, respectively.

The rates of serious adverse events, infections, and serious infections were all similar in the two treatment arms. Infections occurred in 42% of the adalimumab patients and in 48% of those on tocilizumab, and serious infections occurred in 3% of both groups. Serious adverse events occurred in 10% of the adalimumab patients and in 12% of those on tocilizumab. Patients on tocilizumab had moderately higher rates of elevated liver enzymes. The tocilizumab patients had a 31% rate of enzymes elevated from above the upper limit of normal (ULN) to 2.5-fold the ULN, compared with 25% of the adalimumab patients; and liver enzyme elevations of 2.6-5.0 times the ULN occurred in 6% of the tocilizumab patients and in 2% of those on adalimumab. Tocilizumab showed "no new or unexpected adverse effects," Dr. Gabay said.

The study was sponsored by Roche, the company that markets tocilizumab. Dr. Gabay reported receiving research support from and being a consultant to Roche and several other drug companies. Dr. Mariette reported receiving research support from Roche and several other drug companies.

BERLIN – The combination of an elevated level of interferon gene expression and a low level of circulating B cells identified patients with arthralgia who had a high rate of progression to rheumatoid arthritis in a validation study of 115 patients at one center.

After 2 years of follow-up, about 70% of patients with a high level of interferon gene expression and a low level of B cells in their peripheral blood had developed rheumatoid arthritis (RA), while in contrast about 20% of arthralgia patients with low interferon gene expression and a high B-cell level developed RA, Joyce Lubbers said at the annual European Congress of Rheumatology.

Some of Ms. Lubbers’ associates on the study had previously shown, in a different group of 109 patients with arthralgia, that high interferon gene expression was linked to an increased rate of progression to RA, and that high expression of genes involved in B-cell activation was linked to a reduced risk for progressing to RA (Arthritis Rheum. 2010;62:694-704). Hence, the new findings that Ms. Lubbers reported validated the results of the previous study.

"We’ve now shown this in two independent cohorts, and we’re looking at a third group," said Ms. Lubbers, a researcher working on inflammatory disease profiling at VU University Medical Center in Amsterdam.

In practice, these easily obtained lab markers – interferon gene expression and B cell count – can couple with a patient’s clinical profile to estimate the risk of developing RA.

The next step is to test whether an intervention in arthralgia patients at high risk for progression to RA can delay or prevent the progression, or make RA less severe once it develops. Researchers in Amsterdam are currently testing whether treatment of high-risk arthralgia patients with rituximab can have a positive effect on RA progression, she said in an interview.

The study included 115 patients with arthralgia who did not have RA, joint erosions, or a history of treatment with any disease-modifying antirheumatic drug at one center in Amsterdam. During a median 23 months of follow-up, 44 patients (38%) developed RA, after a median of 8 months.

At baseline, the researchers calculated an interferon gene score for each patient, based on their expression of seven different genes involved in responses to interferon. Patients who progressed to RA had an average interferon score at baseline that was about twice the average in the nonprogressors. At 2 years of follow-up, about 60% of the high gene expressors had progressed to RA, compared with about 30% of the low expressors, a statistically significant difference.

Adding data on the number of peripheral blood B cells, quantified by fluorescent-activated cell sorting, produced a statistically significant refinement of the progression rate.

It makes physiologic sense that interferon responses and blood levels of B cells would correlate with progression to early-stage RA, Ms. Lubbers said. A low level of B cells in blood suggests that a higher than normal number of B cells had migrated out of the blood and into tissue, such as into the synovium, Ms. Lubbers said.

Ms. Lubbers said that she had no disclosures. The VU Medical Center has a patent pending on using the markers studied for identifying preclinical RA.

BERLIN – The combination of an elevated level of interferon gene expression and a low level of circulating B cells identified patients with arthralgia who had a high rate of progression to rheumatoid arthritis in a validation study of 115 patients at one center.

After 2 years of follow-up, about 70% of patients with a high level of interferon gene expression and a low level of B cells in their peripheral blood had developed rheumatoid arthritis (RA), while in contrast about 20% of arthralgia patients with low interferon gene expression and a high B-cell level developed RA, Joyce Lubbers said at the annual European Congress of Rheumatology.

Some of Ms. Lubbers’ associates on the study had previously shown, in a different group of 109 patients with arthralgia, that high interferon gene expression was linked to an increased rate of progression to RA, and that high expression of genes involved in B-cell activation was linked to a reduced risk for progressing to RA (Arthritis Rheum. 2010;62:694-704). Hence, the new findings that Ms. Lubbers reported validated the results of the previous study.

"We’ve now shown this in two independent cohorts, and we’re looking at a third group," said Ms. Lubbers, a researcher working on inflammatory disease profiling at VU University Medical Center in Amsterdam.

In practice, these easily obtained lab markers – interferon gene expression and B cell count – can couple with a patient’s clinical profile to estimate the risk of developing RA.

The next step is to test whether an intervention in arthralgia patients at high risk for progression to RA can delay or prevent the progression, or make RA less severe once it develops. Researchers in Amsterdam are currently testing whether treatment of high-risk arthralgia patients with rituximab can have a positive effect on RA progression, she said in an interview.

The study included 115 patients with arthralgia who did not have RA, joint erosions, or a history of treatment with any disease-modifying antirheumatic drug at one center in Amsterdam. During a median 23 months of follow-up, 44 patients (38%) developed RA, after a median of 8 months.

At baseline, the researchers calculated an interferon gene score for each patient, based on their expression of seven different genes involved in responses to interferon. Patients who progressed to RA had an average interferon score at baseline that was about twice the average in the nonprogressors. At 2 years of follow-up, about 60% of the high gene expressors had progressed to RA, compared with about 30% of the low expressors, a statistically significant difference.

Adding data on the number of peripheral blood B cells, quantified by fluorescent-activated cell sorting, produced a statistically significant refinement of the progression rate.

It makes physiologic sense that interferon responses and blood levels of B cells would correlate with progression to early-stage RA, Ms. Lubbers said. A low level of B cells in blood suggests that a higher than normal number of B cells had migrated out of the blood and into tissue, such as into the synovium, Ms. Lubbers said.

Ms. Lubbers said that she had no disclosures. The VU Medical Center has a patent pending on using the markers studied for identifying preclinical RA.

BERLIN – The combination of an elevated level of interferon gene expression and a low level of circulating B cells identified patients with arthralgia who had a high rate of progression to rheumatoid arthritis in a validation study of 115 patients at one center.

After 2 years of follow-up, about 70% of patients with a high level of interferon gene expression and a low level of B cells in their peripheral blood had developed rheumatoid arthritis (RA), while in contrast about 20% of arthralgia patients with low interferon gene expression and a high B-cell level developed RA, Joyce Lubbers said at the annual European Congress of Rheumatology.

Some of Ms. Lubbers’ associates on the study had previously shown, in a different group of 109 patients with arthralgia, that high interferon gene expression was linked to an increased rate of progression to RA, and that high expression of genes involved in B-cell activation was linked to a reduced risk for progressing to RA (Arthritis Rheum. 2010;62:694-704). Hence, the new findings that Ms. Lubbers reported validated the results of the previous study.

"We’ve now shown this in two independent cohorts, and we’re looking at a third group," said Ms. Lubbers, a researcher working on inflammatory disease profiling at VU University Medical Center in Amsterdam.

In practice, these easily obtained lab markers – interferon gene expression and B cell count – can couple with a patient’s clinical profile to estimate the risk of developing RA.

The next step is to test whether an intervention in arthralgia patients at high risk for progression to RA can delay or prevent the progression, or make RA less severe once it develops. Researchers in Amsterdam are currently testing whether treatment of high-risk arthralgia patients with rituximab can have a positive effect on RA progression, she said in an interview.

The study included 115 patients with arthralgia who did not have RA, joint erosions, or a history of treatment with any disease-modifying antirheumatic drug at one center in Amsterdam. During a median 23 months of follow-up, 44 patients (38%) developed RA, after a median of 8 months.

At baseline, the researchers calculated an interferon gene score for each patient, based on their expression of seven different genes involved in responses to interferon. Patients who progressed to RA had an average interferon score at baseline that was about twice the average in the nonprogressors. At 2 years of follow-up, about 60% of the high gene expressors had progressed to RA, compared with about 30% of the low expressors, a statistically significant difference.

Adding data on the number of peripheral blood B cells, quantified by fluorescent-activated cell sorting, produced a statistically significant refinement of the progression rate.

It makes physiologic sense that interferon responses and blood levels of B cells would correlate with progression to early-stage RA, Ms. Lubbers said. A low level of B cells in blood suggests that a higher than normal number of B cells had migrated out of the blood and into tissue, such as into the synovium, Ms. Lubbers said.

Ms. Lubbers said that she had no disclosures. The VU Medical Center has a patent pending on using the markers studied for identifying preclinical RA.

BERLIN – Treated patients in remission from rheumatoid arthritis who are rheumatoid factor–positive and have a high level of joint synovitis visible on MRI have an increased risk for progressive joint damage, according to a review of 287 patients from six international registry cohorts.

The presence of joint synovitis during remission signaled an especially poor prognosis in rheumatoid factor (RF)-positive patients, who accounted for slightly more than half of the group studied. Among rheumatoid arthritis (RA) patients in remission who were RF-positive and had an RA MRI score (RAMRIS) of 6 or more, 42% subsequently had progressive joint erosions, Dr. Espen A. Haavardsholm said at the annual European Congress of Rheumatology.

In contrast, among RF-positive patients in remission with a RAMRIS of 5 or less, 12% had radiographic progression. Among all RF-negative patients, the rate of radiographic progression was less than 20% regardless of their RAMRIS.

What this means is that when RA patients are in remission on treatment, if they are RF-negative their risk of radiographic progression is low and MRI examinations aren’t needed. But if they are RF-positive and if they score 6 or more for synovitis on MRI, their risk for progression is high, and they need close monitoring and no change in their treatment. Patients with a score of 5 or less, as well as those who are RF-negative, are candidates for less rigorous follow-up and a possible step-down in their treatment, said Dr. Haavardsholm, a rheumatologist at Diakohnjemmet Hospital in Oslo.

"When patients are in remission, do you keep them on their current treatment or step down? We suggest you take an MRI and decide based on that," he said in an interview. Although ideally a prospective study should be done to test this approach, "I would manage patients this way right now," Dr. Haavardsholm said. "If a patient [in remission] is RF-positive, they are a good candidate for MRI; that’s the implication of our study."

Dr. Haavardsholm and his associates from the OMERACT (Outcome Measures in Rheumatology) MRI in RA Task Force used data collected on 287 RA patients in remission or with low disease activity on treatment who were in registries in Oslo; Paris; Sydney; Leeds, England; and two different cohorts in Copenhagen. The patients ranged from 43 to 63 years old, and their average RA duration was about 2 years. Virtually all patients were on treatment with a disease-modifying antirheumatic drug, 15% were also on treatment with a biologic agent, and a quarter were on an oral corticosteroid. Nearly three-quarters were in remission, with the rest having low disease activity. The researchers had baseline MRI results for all patients.

A multivariate stepwise regression analysis and calculation of a receiver-operator curve for various cutoffs of the RAMRIS for synovitis showed that best dichotomous separation occurred when a RAMRIS of 0-5 was considered low and a score of 6 or more was considered high. Using this cutoff, the researchers found that among RF-positive patients, those with a score of at least 6 had a 4.4-fold increased risk for progressive joint disease compared with patients with a baseline score of 5 or less, a statistically significant difference, Dr. Haavardsholm reported. Among patients who were RF-negative, a RAMRIS of 6 or more boosted the risk for joint progression by 9% compared with patients with a score of 5 or less, a difference that was not statistically significant.

Dr. Haavardsholm said that he had no disclosures.

BERLIN – Treated patients in remission from rheumatoid arthritis who are rheumatoid factor–positive and have a high level of joint synovitis visible on MRI have an increased risk for progressive joint damage, according to a review of 287 patients from six international registry cohorts.

The presence of joint synovitis during remission signaled an especially poor prognosis in rheumatoid factor (RF)-positive patients, who accounted for slightly more than half of the group studied. Among rheumatoid arthritis (RA) patients in remission who were RF-positive and had an RA MRI score (RAMRIS) of 6 or more, 42% subsequently had progressive joint erosions, Dr. Espen A. Haavardsholm said at the annual European Congress of Rheumatology.

In contrast, among RF-positive patients in remission with a RAMRIS of 5 or less, 12% had radiographic progression. Among all RF-negative patients, the rate of radiographic progression was less than 20% regardless of their RAMRIS.

What this means is that when RA patients are in remission on treatment, if they are RF-negative their risk of radiographic progression is low and MRI examinations aren’t needed. But if they are RF-positive and if they score 6 or more for synovitis on MRI, their risk for progression is high, and they need close monitoring and no change in their treatment. Patients with a score of 5 or less, as well as those who are RF-negative, are candidates for less rigorous follow-up and a possible step-down in their treatment, said Dr. Haavardsholm, a rheumatologist at Diakohnjemmet Hospital in Oslo.

"When patients are in remission, do you keep them on their current treatment or step down? We suggest you take an MRI and decide based on that," he said in an interview. Although ideally a prospective study should be done to test this approach, "I would manage patients this way right now," Dr. Haavardsholm said. "If a patient [in remission] is RF-positive, they are a good candidate for MRI; that’s the implication of our study."

Dr. Haavardsholm and his associates from the OMERACT (Outcome Measures in Rheumatology) MRI in RA Task Force used data collected on 287 RA patients in remission or with low disease activity on treatment who were in registries in Oslo; Paris; Sydney; Leeds, England; and two different cohorts in Copenhagen. The patients ranged from 43 to 63 years old, and their average RA duration was about 2 years. Virtually all patients were on treatment with a disease-modifying antirheumatic drug, 15% were also on treatment with a biologic agent, and a quarter were on an oral corticosteroid. Nearly three-quarters were in remission, with the rest having low disease activity. The researchers had baseline MRI results for all patients.

A multivariate stepwise regression analysis and calculation of a receiver-operator curve for various cutoffs of the RAMRIS for synovitis showed that best dichotomous separation occurred when a RAMRIS of 0-5 was considered low and a score of 6 or more was considered high. Using this cutoff, the researchers found that among RF-positive patients, those with a score of at least 6 had a 4.4-fold increased risk for progressive joint disease compared with patients with a baseline score of 5 or less, a statistically significant difference, Dr. Haavardsholm reported. Among patients who were RF-negative, a RAMRIS of 6 or more boosted the risk for joint progression by 9% compared with patients with a score of 5 or less, a difference that was not statistically significant.

Dr. Haavardsholm said that he had no disclosures.

BERLIN – Treated patients in remission from rheumatoid arthritis who are rheumatoid factor–positive and have a high level of joint synovitis visible on MRI have an increased risk for progressive joint damage, according to a review of 287 patients from six international registry cohorts.

The presence of joint synovitis during remission signaled an especially poor prognosis in rheumatoid factor (RF)-positive patients, who accounted for slightly more than half of the group studied. Among rheumatoid arthritis (RA) patients in remission who were RF-positive and had an RA MRI score (RAMRIS) of 6 or more, 42% subsequently had progressive joint erosions, Dr. Espen A. Haavardsholm said at the annual European Congress of Rheumatology.

In contrast, among RF-positive patients in remission with a RAMRIS of 5 or less, 12% had radiographic progression. Among all RF-negative patients, the rate of radiographic progression was less than 20% regardless of their RAMRIS.

What this means is that when RA patients are in remission on treatment, if they are RF-negative their risk of radiographic progression is low and MRI examinations aren’t needed. But if they are RF-positive and if they score 6 or more for synovitis on MRI, their risk for progression is high, and they need close monitoring and no change in their treatment. Patients with a score of 5 or less, as well as those who are RF-negative, are candidates for less rigorous follow-up and a possible step-down in their treatment, said Dr. Haavardsholm, a rheumatologist at Diakohnjemmet Hospital in Oslo.

"When patients are in remission, do you keep them on their current treatment or step down? We suggest you take an MRI and decide based on that," he said in an interview. Although ideally a prospective study should be done to test this approach, "I would manage patients this way right now," Dr. Haavardsholm said. "If a patient [in remission] is RF-positive, they are a good candidate for MRI; that’s the implication of our study."

Dr. Haavardsholm and his associates from the OMERACT (Outcome Measures in Rheumatology) MRI in RA Task Force used data collected on 287 RA patients in remission or with low disease activity on treatment who were in registries in Oslo; Paris; Sydney; Leeds, England; and two different cohorts in Copenhagen. The patients ranged from 43 to 63 years old, and their average RA duration was about 2 years. Virtually all patients were on treatment with a disease-modifying antirheumatic drug, 15% were also on treatment with a biologic agent, and a quarter were on an oral corticosteroid. Nearly three-quarters were in remission, with the rest having low disease activity. The researchers had baseline MRI results for all patients.

A multivariate stepwise regression analysis and calculation of a receiver-operator curve for various cutoffs of the RAMRIS for synovitis showed that best dichotomous separation occurred when a RAMRIS of 0-5 was considered low and a score of 6 or more was considered high. Using this cutoff, the researchers found that among RF-positive patients, those with a score of at least 6 had a 4.4-fold increased risk for progressive joint disease compared with patients with a baseline score of 5 or less, a statistically significant difference, Dr. Haavardsholm reported. Among patients who were RF-negative, a RAMRIS of 6 or more boosted the risk for joint progression by 9% compared with patients with a score of 5 or less, a difference that was not statistically significant.

Dr. Haavardsholm said that he had no disclosures.

BERLIN – A recently identified polymorphism in the fibroblast growth factor 23 gene may be a useful predictor of high risk for coronary artery damage in patients with Kawasaki disease.

Fibroblast growth factor is a phosphorus-regulating hormone. Fibroblast growth factor 23 (FGF23) has previously been identified as a contributor to left ventricular hypertrophy in patients with chronic kidney disease (Circulation 2009;119:2545-52), and as having a possible role in the atherosclerotic process as well. There are FGF23 receptors in the vasculature and in the heart, Dr. Fernanda Falcini explained at the annual European Congress of Rheumatology.

She and her coinvestigators have recently identified an FGF23 polymorphism involving a C insertion in the intronic region between nucleotides 36 and 37. Now they have implicated the polymorphism as having a possible functional role in the predisposition to coronary artery disease in patients with Kawasaki disease.

First the investigators demonstrated that the polymorphism was present in 35% of 100 healthy Italian white subjects. Then they extended their DNA analysis to 118 white patients with Kawasaki disease and 76 age- and sex-matched healthy control children.

The Kawasaki disease patients (median age, 33 months) underwent two-dimensional echocardiography at hospital admission, at day 15, and at 2, 6, and 12 months. Coronary artery damage in the form of an aneurysm or global dilation developed in 28 of the 118 patients.

Of patients with Kawasaki disease, 31% possessed the FGF23 polymorphism. Strikingly, the polymorphism was present in 24 of the 28 patients (86%) with coronary artery disease, but in only 12 of 90 (13%) with normal arteries, reported Dr. Falcini, a rheumatologist at the University of Florence (Italy).

Moreover, Kawasaki disease patients with the FGF23 polymorphism had significantly higher serum FGF23 levels than those with the wildtype FGF23 gene: a mean of 120, compared with 38 pg/mL. How those substantially higher serum levels of the hormone relate to coronary artery damage in patients with Kawasaki disease is a top research priority.

Coronary artery involvement is the most serious and long-lasting complication of Kawasaki disease, and the biggest contributor to the disease’s increased mortality risk. The etiology of the coronary artery damage remains unknown. The leading theory is that an infectious agent elicits a massive systemic inflammatory response directed at cardiovascular tissues. The ability to identify the patient subgroup at high risk for coronary artery damage would enable physicians to develop an aggressive, selectively applied prevention strategy.

The study was funded by an Italian medical research foundation. Dr. Falcini reported having no relevant financial conflicts.

BERLIN – A recently identified polymorphism in the fibroblast growth factor 23 gene may be a useful predictor of high risk for coronary artery damage in patients with Kawasaki disease.

Fibroblast growth factor is a phosphorus-regulating hormone. Fibroblast growth factor 23 (FGF23) has previously been identified as a contributor to left ventricular hypertrophy in patients with chronic kidney disease (Circulation 2009;119:2545-52), and as having a possible role in the atherosclerotic process as well. There are FGF23 receptors in the vasculature and in the heart, Dr. Fernanda Falcini explained at the annual European Congress of Rheumatology.

She and her coinvestigators have recently identified an FGF23 polymorphism involving a C insertion in the intronic region between nucleotides 36 and 37. Now they have implicated the polymorphism as having a possible functional role in the predisposition to coronary artery disease in patients with Kawasaki disease.

First the investigators demonstrated that the polymorphism was present in 35% of 100 healthy Italian white subjects. Then they extended their DNA analysis to 118 white patients with Kawasaki disease and 76 age- and sex-matched healthy control children.

The Kawasaki disease patients (median age, 33 months) underwent two-dimensional echocardiography at hospital admission, at day 15, and at 2, 6, and 12 months. Coronary artery damage in the form of an aneurysm or global dilation developed in 28 of the 118 patients.

Of patients with Kawasaki disease, 31% possessed the FGF23 polymorphism. Strikingly, the polymorphism was present in 24 of the 28 patients (86%) with coronary artery disease, but in only 12 of 90 (13%) with normal arteries, reported Dr. Falcini, a rheumatologist at the University of Florence (Italy).

Moreover, Kawasaki disease patients with the FGF23 polymorphism had significantly higher serum FGF23 levels than those with the wildtype FGF23 gene: a mean of 120, compared with 38 pg/mL. How those substantially higher serum levels of the hormone relate to coronary artery damage in patients with Kawasaki disease is a top research priority.

Coronary artery involvement is the most serious and long-lasting complication of Kawasaki disease, and the biggest contributor to the disease’s increased mortality risk. The etiology of the coronary artery damage remains unknown. The leading theory is that an infectious agent elicits a massive systemic inflammatory response directed at cardiovascular tissues. The ability to identify the patient subgroup at high risk for coronary artery damage would enable physicians to develop an aggressive, selectively applied prevention strategy.

The study was funded by an Italian medical research foundation. Dr. Falcini reported having no relevant financial conflicts.

BERLIN – A recently identified polymorphism in the fibroblast growth factor 23 gene may be a useful predictor of high risk for coronary artery damage in patients with Kawasaki disease.

Fibroblast growth factor is a phosphorus-regulating hormone. Fibroblast growth factor 23 (FGF23) has previously been identified as a contributor to left ventricular hypertrophy in patients with chronic kidney disease (Circulation 2009;119:2545-52), and as having a possible role in the atherosclerotic process as well. There are FGF23 receptors in the vasculature and in the heart, Dr. Fernanda Falcini explained at the annual European Congress of Rheumatology.

She and her coinvestigators have recently identified an FGF23 polymorphism involving a C insertion in the intronic region between nucleotides 36 and 37. Now they have implicated the polymorphism as having a possible functional role in the predisposition to coronary artery disease in patients with Kawasaki disease.

First the investigators demonstrated that the polymorphism was present in 35% of 100 healthy Italian white subjects. Then they extended their DNA analysis to 118 white patients with Kawasaki disease and 76 age- and sex-matched healthy control children.

The Kawasaki disease patients (median age, 33 months) underwent two-dimensional echocardiography at hospital admission, at day 15, and at 2, 6, and 12 months. Coronary artery damage in the form of an aneurysm or global dilation developed in 28 of the 118 patients.

Of patients with Kawasaki disease, 31% possessed the FGF23 polymorphism. Strikingly, the polymorphism was present in 24 of the 28 patients (86%) with coronary artery disease, but in only 12 of 90 (13%) with normal arteries, reported Dr. Falcini, a rheumatologist at the University of Florence (Italy).

Moreover, Kawasaki disease patients with the FGF23 polymorphism had significantly higher serum FGF23 levels than those with the wildtype FGF23 gene: a mean of 120, compared with 38 pg/mL. How those substantially higher serum levels of the hormone relate to coronary artery damage in patients with Kawasaki disease is a top research priority.

Coronary artery involvement is the most serious and long-lasting complication of Kawasaki disease, and the biggest contributor to the disease’s increased mortality risk. The etiology of the coronary artery damage remains unknown. The leading theory is that an infectious agent elicits a massive systemic inflammatory response directed at cardiovascular tissues. The ability to identify the patient subgroup at high risk for coronary artery damage would enable physicians to develop an aggressive, selectively applied prevention strategy.

The study was funded by an Italian medical research foundation. Dr. Falcini reported having no relevant financial conflicts.

BERLIN – Two new Janus kinase inhibitor drugs have shown good safety and efficacy for clinical rheumatoid arthritis, following in the footsteps of the JAK inhibitor tofacitinib, researchers reported at the annual European Congress of Rheumatology.

Baricitinib showed safety and promising efficacy in a multicenter, phase 2 study with 301 rheumatoid arthritis (RA) patients, said Dr. Edward Keystone, professor of medicine at the University of Toronto. And in results from a second study, GLPG0634 showed good safety and efficacy in a placebo-controlled, early phase 2 study with 36 RA patients. In both cases the results should propel these drugs into wider clinical testing.

Mitchel Zoler/IMNG Medical Media

The results also hinted that different JAK inhibitors may produce somewhat different clinical effects depending on exactly which Janus kinases they inhibit. Tofacitinib blocks all four JAKs, but its effect seems strongest on JAK3. Baricitinib specifically inhibits JAK1 and JAK2, while GLPG0634 specifically inhibits only JAK1, said speakers at the meeting.

"JAK selectivity makes a difference," said Dr. Frédéric Vanhoutte, lead investigator of the GLPG0634 study and a staff member at Galapagos, the Belgium drug company developing the agent.

The baricitinib study randomized patients on methotrexate to any of four drug dosages, given as a single, daily oral treatment, or placebo and looked at safety and efficacy after 12 weeks on treatment. At 12 weeks 76% of patients treated with either of the two highest baricitinib dosages (4 mg or 8 mg daily) had an American College of Rheumatology (ACR) 20 response, compared with 41% of the placebo patients, a statistically significant difference for the study’s primary end point, reported Dr. Keystone, who also directs the center for arthritis and autoimmune disease at Mount Sinai Hospital in Toronto. The incidence of remission at 12 weeks, based on a simple disease activity index (SDAI) score of 3.3 or less, occurred in 18% of patients on the 4-mg/day baricitinib plus methotrexate regimen compared with 1% of patients on methotrexate and placebo; 8% of patients who received 8 mg daily also achieved remission.

For safety, baricitinib appeared well tolerated, with an adverse event profile similar to the placebo arm. The results showed dose-dependent reductions in hemoglobin and neutrophils, and an increased level of low density lipoprotein cholesterol, but effects that surpassed the placebo arm primarily occurred in patients who received 8 mg of the drug daily. "The reductions in hemoglobin and neutrophils were of the same order of magnitude as with tofacitinib," Dr. Keystone said in an interview. "Some had thought that baricitinib might be more inhibitory to the hematologic system than tofacitinib, but it wasn’t very."

The study of 36 RA patients on methotrexate who received either of two dosages of the oral JAK 1 inhibitor GLPG0634 or placebo ran for 4 weeks at one center in Europe. The 100-mg b.i.d. dosage led to 92% of patients meeting ACR 20 criteria after 4 weeks, compared with 75% of patients who received 200 mg once daily and 33% among placebo patients, reported Dr. Vanhoutte. Treatment with the JAK1 inhibitor also led to higher remission rates and drops in C-reactive protein.

For safety, the JAK1 inhibitor actually boosted hemoglobin levels, led to no rise in LDL cholesterol or liver enzymes, and produced a "modest" reduction in neutrophils and platelets. Dr. Vanhoutte called the overall safety results "very encouraging."

The baricitinib trial was sponsored by Lilly, the company developing the drug. Dr. Keystone said that he has received research support from Lilly, and that he has received research support and has served as a consultant for several other drug companies. The GLPG0634 study was sponsored by Galapagos. Dr. Vanhoutte said that he is an employee of Galapagos.

BERLIN – Two new Janus kinase inhibitor drugs have shown good safety and efficacy for clinical rheumatoid arthritis, following in the footsteps of the JAK inhibitor tofacitinib, researchers reported at the annual European Congress of Rheumatology.

Baricitinib showed safety and promising efficacy in a multicenter, phase 2 study with 301 rheumatoid arthritis (RA) patients, said Dr. Edward Keystone, professor of medicine at the University of Toronto. And in results from a second study, GLPG0634 showed good safety and efficacy in a placebo-controlled, early phase 2 study with 36 RA patients. In both cases the results should propel these drugs into wider clinical testing.

Mitchel Zoler/IMNG Medical Media

The results also hinted that different JAK inhibitors may produce somewhat different clinical effects depending on exactly which Janus kinases they inhibit. Tofacitinib blocks all four JAKs, but its effect seems strongest on JAK3. Baricitinib specifically inhibits JAK1 and JAK2, while GLPG0634 specifically inhibits only JAK1, said speakers at the meeting.

"JAK selectivity makes a difference," said Dr. Frédéric Vanhoutte, lead investigator of the GLPG0634 study and a staff member at Galapagos, the Belgium drug company developing the agent.

The baricitinib study randomized patients on methotrexate to any of four drug dosages, given as a single, daily oral treatment, or placebo and looked at safety and efficacy after 12 weeks on treatment. At 12 weeks 76% of patients treated with either of the two highest baricitinib dosages (4 mg or 8 mg daily) had an American College of Rheumatology (ACR) 20 response, compared with 41% of the placebo patients, a statistically significant difference for the study’s primary end point, reported Dr. Keystone, who also directs the center for arthritis and autoimmune disease at Mount Sinai Hospital in Toronto. The incidence of remission at 12 weeks, based on a simple disease activity index (SDAI) score of 3.3 or less, occurred in 18% of patients on the 4-mg/day baricitinib plus methotrexate regimen compared with 1% of patients on methotrexate and placebo; 8% of patients who received 8 mg daily also achieved remission.

For safety, baricitinib appeared well tolerated, with an adverse event profile similar to the placebo arm. The results showed dose-dependent reductions in hemoglobin and neutrophils, and an increased level of low density lipoprotein cholesterol, but effects that surpassed the placebo arm primarily occurred in patients who received 8 mg of the drug daily. "The reductions in hemoglobin and neutrophils were of the same order of magnitude as with tofacitinib," Dr. Keystone said in an interview. "Some had thought that baricitinib might be more inhibitory to the hematologic system than tofacitinib, but it wasn’t very."

The study of 36 RA patients on methotrexate who received either of two dosages of the oral JAK 1 inhibitor GLPG0634 or placebo ran for 4 weeks at one center in Europe. The 100-mg b.i.d. dosage led to 92% of patients meeting ACR 20 criteria after 4 weeks, compared with 75% of patients who received 200 mg once daily and 33% among placebo patients, reported Dr. Vanhoutte. Treatment with the JAK1 inhibitor also led to higher remission rates and drops in C-reactive protein.

For safety, the JAK1 inhibitor actually boosted hemoglobin levels, led to no rise in LDL cholesterol or liver enzymes, and produced a "modest" reduction in neutrophils and platelets. Dr. Vanhoutte called the overall safety results "very encouraging."

The baricitinib trial was sponsored by Lilly, the company developing the drug. Dr. Keystone said that he has received research support from Lilly, and that he has received research support and has served as a consultant for several other drug companies. The GLPG0634 study was sponsored by Galapagos. Dr. Vanhoutte said that he is an employee of Galapagos.

BERLIN – Two new Janus kinase inhibitor drugs have shown good safety and efficacy for clinical rheumatoid arthritis, following in the footsteps of the JAK inhibitor tofacitinib, researchers reported at the annual European Congress of Rheumatology.

Baricitinib showed safety and promising efficacy in a multicenter, phase 2 study with 301 rheumatoid arthritis (RA) patients, said Dr. Edward Keystone, professor of medicine at the University of Toronto. And in results from a second study, GLPG0634 showed good safety and efficacy in a placebo-controlled, early phase 2 study with 36 RA patients. In both cases the results should propel these drugs into wider clinical testing.

Mitchel Zoler/IMNG Medical Media

The results also hinted that different JAK inhibitors may produce somewhat different clinical effects depending on exactly which Janus kinases they inhibit. Tofacitinib blocks all four JAKs, but its effect seems strongest on JAK3. Baricitinib specifically inhibits JAK1 and JAK2, while GLPG0634 specifically inhibits only JAK1, said speakers at the meeting.

"JAK selectivity makes a difference," said Dr. Frédéric Vanhoutte, lead investigator of the GLPG0634 study and a staff member at Galapagos, the Belgium drug company developing the agent.

The baricitinib study randomized patients on methotrexate to any of four drug dosages, given as a single, daily oral treatment, or placebo and looked at safety and efficacy after 12 weeks on treatment. At 12 weeks 76% of patients treated with either of the two highest baricitinib dosages (4 mg or 8 mg daily) had an American College of Rheumatology (ACR) 20 response, compared with 41% of the placebo patients, a statistically significant difference for the study’s primary end point, reported Dr. Keystone, who also directs the center for arthritis and autoimmune disease at Mount Sinai Hospital in Toronto. The incidence of remission at 12 weeks, based on a simple disease activity index (SDAI) score of 3.3 or less, occurred in 18% of patients on the 4-mg/day baricitinib plus methotrexate regimen compared with 1% of patients on methotrexate and placebo; 8% of patients who received 8 mg daily also achieved remission.

For safety, baricitinib appeared well tolerated, with an adverse event profile similar to the placebo arm. The results showed dose-dependent reductions in hemoglobin and neutrophils, and an increased level of low density lipoprotein cholesterol, but effects that surpassed the placebo arm primarily occurred in patients who received 8 mg of the drug daily. "The reductions in hemoglobin and neutrophils were of the same order of magnitude as with tofacitinib," Dr. Keystone said in an interview. "Some had thought that baricitinib might be more inhibitory to the hematologic system than tofacitinib, but it wasn’t very."

The study of 36 RA patients on methotrexate who received either of two dosages of the oral JAK 1 inhibitor GLPG0634 or placebo ran for 4 weeks at one center in Europe. The 100-mg b.i.d. dosage led to 92% of patients meeting ACR 20 criteria after 4 weeks, compared with 75% of patients who received 200 mg once daily and 33% among placebo patients, reported Dr. Vanhoutte. Treatment with the JAK1 inhibitor also led to higher remission rates and drops in C-reactive protein.

For safety, the JAK1 inhibitor actually boosted hemoglobin levels, led to no rise in LDL cholesterol or liver enzymes, and produced a "modest" reduction in neutrophils and platelets. Dr. Vanhoutte called the overall safety results "very encouraging."

The baricitinib trial was sponsored by Lilly, the company developing the drug. Dr. Keystone said that he has received research support from Lilly, and that he has received research support and has served as a consultant for several other drug companies. The GLPG0634 study was sponsored by Galapagos. Dr. Vanhoutte said that he is an employee of Galapagos.

BERLIN – Most patients with long-standing rheumatoid arthritis or other rheumatic diseases and in remission while on an anti–tumor necrosis factor drug could successfully undergo dose reduction and stay in remission, based on experience with 90 patients at one U.K. center.

In addition to maintaining a majority of patients on a reduced biologic regimen, a step that pleased patients, the program produced substantial cost savings, cutting drug costs in the unit by more than $400,000 during the course of 1 year, Dr. Jane Gibson said at the annual meeting of the European Congress of Rheumatology.

Out of 90 patients with rheumatoid arthritis (RA) or another rheumatic disease and in remission for more than a year and on a stable, standard regimen with etanercept or adalimumab, 68 (76%) successfully underwent a dosage reduction and remained in remission, said Dr. Gibson, head of the Fife Rheumatic Diseases Unit, part of the U.K. National Health Service serving the county of Fife in Scotland.

The sixteen patients who failed to stay in remission while on a reduced dosage of an anti–tumor necrosis factor (anti-TNF) drug were all successfully put back into remission with a corticosteroid injection and reinstitution of their prior treatment. Another six patients stopped their anti-TNF regimen for unrelated reasons during the period of the study, December 2010 to December 2011.

"These were patients with very long-standing disease, with some patients having RA for more than 40 years. The patients loved it; they felt it was a positive step. That was a big surprise because I thought that I’d have to persuade patients, but they thought it was great," Dr. Gibson said in an interview.

A regression analysis identified several factors significantly linked with an increased likelihood of patients’ successfully undergoing a dose reduction and remaining in remission. The strongest link was for concomitant treatment with methotrexate, according to Dr. Gibson and her associates. Patients who received methotrexate along with the anti-TNF drug had a substantially better rate of continued remission once the anti-TNF dosage dropped. Other statistically significant factors linked with successful dose reduction were concomitant treatment with any disease modifying anti-rheumatic drug (DMARD), and treatment with adalimumab (compared with treatment with etanercept). In addition, smoking history showed a strong trend toward a better rate of remission among never smokers or former smokers, but this did not reach statistical significance.

Dr. Gibson cautioned that any difference in the durability of remission on adalimumab compared with etanercept might result from the substantially shorter clinical half-lives of the two drugs. Etanercept has a half-life of 3-4 days, so cutting the dosage from the standard 50 mg subcutaneously once per week to 50 mg once every 2 weeks meant that patients scaled back to roughly four times the drug’s half-life. Thirteen of the 16 failed remissions occurred among patients switched to 50 mg etanercept every 2 weeks; among four patients scaled back to 50 mg etanercept administered every 10 days, none fell out of remission, Dr. Gibson said.

In contrast, adalimumab’s clinical half-life is about 14 days, so scaling back from the standard dosage of 40 mg subcutaneously every 2 weeks to the same amount given every 4 weeks meant that patients received the drug at intervals twice as long as the half-life. None of the 14 patients who received adalimumab every 4 weeks fell out of remission, and just two of 16 patients came out of remission when scaled back to a dosage of 40 mg adalimumab every 3 weeks.

Although concomitant methotrexate was the strongest predictor of success with scaled back dosing, only about half the patients in the Fife series were on methotrexate, and nearly a third were not on any concomitant DMARD, and so Dr. Gibson said she was unsure about any ironclad need to get patients on methotrexate or another DMARD before attempting to scale back the frequency of use of an anti-TNF agent. She said that she would attempt a small cut in anti-TNF dosage – to etanercept every 10 days or adalimumab every 3 weeks – even in patients not on a DMARD, especially if they were not current smokers, she said, although she would also frequently review these patients to watch for signs of a flare.

The premise of the approach is: "Why keep patients at the same dose? Why not see if we can adjust it?" she said.

The 84 rheumatic-disease patients who underwent an anti-TNF dose-adjustment included three-quarters with RA, with most other patients having psoriatic arthritis or ankylosing spondylitis. The average age was 57 years. Mean disease duration was more than 15 years. Their average time in continued remission at a reduced anti-TNF dosage was 11 months, with one patient followed for almost 3 years. Patients who fell out of remission tended to do so quickly, after an average of less than 4 months, and with only one patient taking longer than 5 months to fail.

Dr. Gibson said that she had no disclosures.

BERLIN – Most patients with long-standing rheumatoid arthritis or other rheumatic diseases and in remission while on an anti–tumor necrosis factor drug could successfully undergo dose reduction and stay in remission, based on experience with 90 patients at one U.K. center.

In addition to maintaining a majority of patients on a reduced biologic regimen, a step that pleased patients, the program produced substantial cost savings, cutting drug costs in the unit by more than $400,000 during the course of 1 year, Dr. Jane Gibson said at the annual meeting of the European Congress of Rheumatology.

Out of 90 patients with rheumatoid arthritis (RA) or another rheumatic disease and in remission for more than a year and on a stable, standard regimen with etanercept or adalimumab, 68 (76%) successfully underwent a dosage reduction and remained in remission, said Dr. Gibson, head of the Fife Rheumatic Diseases Unit, part of the U.K. National Health Service serving the county of Fife in Scotland.

The sixteen patients who failed to stay in remission while on a reduced dosage of an anti–tumor necrosis factor (anti-TNF) drug were all successfully put back into remission with a corticosteroid injection and reinstitution of their prior treatment. Another six patients stopped their anti-TNF regimen for unrelated reasons during the period of the study, December 2010 to December 2011.

"These were patients with very long-standing disease, with some patients having RA for more than 40 years. The patients loved it; they felt it was a positive step. That was a big surprise because I thought that I’d have to persuade patients, but they thought it was great," Dr. Gibson said in an interview.

A regression analysis identified several factors significantly linked with an increased likelihood of patients’ successfully undergoing a dose reduction and remaining in remission. The strongest link was for concomitant treatment with methotrexate, according to Dr. Gibson and her associates. Patients who received methotrexate along with the anti-TNF drug had a substantially better rate of continued remission once the anti-TNF dosage dropped. Other statistically significant factors linked with successful dose reduction were concomitant treatment with any disease modifying anti-rheumatic drug (DMARD), and treatment with adalimumab (compared with treatment with etanercept). In addition, smoking history showed a strong trend toward a better rate of remission among never smokers or former smokers, but this did not reach statistical significance.

Dr. Gibson cautioned that any difference in the durability of remission on adalimumab compared with etanercept might result from the substantially shorter clinical half-lives of the two drugs. Etanercept has a half-life of 3-4 days, so cutting the dosage from the standard 50 mg subcutaneously once per week to 50 mg once every 2 weeks meant that patients scaled back to roughly four times the drug’s half-life. Thirteen of the 16 failed remissions occurred among patients switched to 50 mg etanercept every 2 weeks; among four patients scaled back to 50 mg etanercept administered every 10 days, none fell out of remission, Dr. Gibson said.

In contrast, adalimumab’s clinical half-life is about 14 days, so scaling back from the standard dosage of 40 mg subcutaneously every 2 weeks to the same amount given every 4 weeks meant that patients received the drug at intervals twice as long as the half-life. None of the 14 patients who received adalimumab every 4 weeks fell out of remission, and just two of 16 patients came out of remission when scaled back to a dosage of 40 mg adalimumab every 3 weeks.

Although concomitant methotrexate was the strongest predictor of success with scaled back dosing, only about half the patients in the Fife series were on methotrexate, and nearly a third were not on any concomitant DMARD, and so Dr. Gibson said she was unsure about any ironclad need to get patients on methotrexate or another DMARD before attempting to scale back the frequency of use of an anti-TNF agent. She said that she would attempt a small cut in anti-TNF dosage – to etanercept every 10 days or adalimumab every 3 weeks – even in patients not on a DMARD, especially if they were not current smokers, she said, although she would also frequently review these patients to watch for signs of a flare.

The premise of the approach is: "Why keep patients at the same dose? Why not see if we can adjust it?" she said.

The 84 rheumatic-disease patients who underwent an anti-TNF dose-adjustment included three-quarters with RA, with most other patients having psoriatic arthritis or ankylosing spondylitis. The average age was 57 years. Mean disease duration was more than 15 years. Their average time in continued remission at a reduced anti-TNF dosage was 11 months, with one patient followed for almost 3 years. Patients who fell out of remission tended to do so quickly, after an average of less than 4 months, and with only one patient taking longer than 5 months to fail.

Dr. Gibson said that she had no disclosures.

BERLIN – Most patients with long-standing rheumatoid arthritis or other rheumatic diseases and in remission while on an anti–tumor necrosis factor drug could successfully undergo dose reduction and stay in remission, based on experience with 90 patients at one U.K. center.

In addition to maintaining a majority of patients on a reduced biologic regimen, a step that pleased patients, the program produced substantial cost savings, cutting drug costs in the unit by more than $400,000 during the course of 1 year, Dr. Jane Gibson said at the annual meeting of the European Congress of Rheumatology.

Out of 90 patients with rheumatoid arthritis (RA) or another rheumatic disease and in remission for more than a year and on a stable, standard regimen with etanercept or adalimumab, 68 (76%) successfully underwent a dosage reduction and remained in remission, said Dr. Gibson, head of the Fife Rheumatic Diseases Unit, part of the U.K. National Health Service serving the county of Fife in Scotland.

The sixteen patients who failed to stay in remission while on a reduced dosage of an anti–tumor necrosis factor (anti-TNF) drug were all successfully put back into remission with a corticosteroid injection and reinstitution of their prior treatment. Another six patients stopped their anti-TNF regimen for unrelated reasons during the period of the study, December 2010 to December 2011.

"These were patients with very long-standing disease, with some patients having RA for more than 40 years. The patients loved it; they felt it was a positive step. That was a big surprise because I thought that I’d have to persuade patients, but they thought it was great," Dr. Gibson said in an interview.

A regression analysis identified several factors significantly linked with an increased likelihood of patients’ successfully undergoing a dose reduction and remaining in remission. The strongest link was for concomitant treatment with methotrexate, according to Dr. Gibson and her associates. Patients who received methotrexate along with the anti-TNF drug had a substantially better rate of continued remission once the anti-TNF dosage dropped. Other statistically significant factors linked with successful dose reduction were concomitant treatment with any disease modifying anti-rheumatic drug (DMARD), and treatment with adalimumab (compared with treatment with etanercept). In addition, smoking history showed a strong trend toward a better rate of remission among never smokers or former smokers, but this did not reach statistical significance.

Dr. Gibson cautioned that any difference in the durability of remission on adalimumab compared with etanercept might result from the substantially shorter clinical half-lives of the two drugs. Etanercept has a half-life of 3-4 days, so cutting the dosage from the standard 50 mg subcutaneously once per week to 50 mg once every 2 weeks meant that patients scaled back to roughly four times the drug’s half-life. Thirteen of the 16 failed remissions occurred among patients switched to 50 mg etanercept every 2 weeks; among four patients scaled back to 50 mg etanercept administered every 10 days, none fell out of remission, Dr. Gibson said.

In contrast, adalimumab’s clinical half-life is about 14 days, so scaling back from the standard dosage of 40 mg subcutaneously every 2 weeks to the same amount given every 4 weeks meant that patients received the drug at intervals twice as long as the half-life. None of the 14 patients who received adalimumab every 4 weeks fell out of remission, and just two of 16 patients came out of remission when scaled back to a dosage of 40 mg adalimumab every 3 weeks.

Although concomitant methotrexate was the strongest predictor of success with scaled back dosing, only about half the patients in the Fife series were on methotrexate, and nearly a third were not on any concomitant DMARD, and so Dr. Gibson said she was unsure about any ironclad need to get patients on methotrexate or another DMARD before attempting to scale back the frequency of use of an anti-TNF agent. She said that she would attempt a small cut in anti-TNF dosage – to etanercept every 10 days or adalimumab every 3 weeks – even in patients not on a DMARD, especially if they were not current smokers, she said, although she would also frequently review these patients to watch for signs of a flare.

The premise of the approach is: "Why keep patients at the same dose? Why not see if we can adjust it?" she said.

The 84 rheumatic-disease patients who underwent an anti-TNF dose-adjustment included three-quarters with RA, with most other patients having psoriatic arthritis or ankylosing spondylitis. The average age was 57 years. Mean disease duration was more than 15 years. Their average time in continued remission at a reduced anti-TNF dosage was 11 months, with one patient followed for almost 3 years. Patients who fell out of remission tended to do so quickly, after an average of less than 4 months, and with only one patient taking longer than 5 months to fail.

Dr. Gibson said that she had no disclosures.

BERLIN – The notion of a tocilizumab-based treatment strategy without the use of methotrexate in rheumatoid arthritis patients having an inadequate response to methotrexate monotherapy has lost some of its allure in light of 52-week data from the phase IIIb ACT-RAY trial.

Preliminary results of the randomized, double-blind study reported at last fall’s annual meeting of the American College of Rheumatology showed similar clinical improvement in patients with a prior inadequate response to methotrexate alone regardless of whether they received 24 weeks of methotrexate plus tocilizumab (Actemra) or tocilizumab plus placebo. But by the 52-week mark, things had changed, Dr. Maxime Dougados reported at the annual European Congress of Rheumatology.

At 52 weeks in the 556-patient trial, the DAS28 remission rate, defined as a DAS28 score below 2.6, had been achieved by 45.5% of patients assigned to methotrexate plus tocilizumab at 8 mg/kg given intravenously every 4 weeks, a significantly better outcome than the 36.6% rate in patients on the interleukin-6 inhibitor plus an oral placebo in lieu of methotrexate.

Moreover, while 92.4% of patients assigned to tocilizumab/methotrexate combination therapy were free of radiographic disease progression at 1 year, that was true for only 85.5% of those on tocilizumab plus placebo (P = .007).

This doesn’t mean the end for a tocilizumab-based, methotrexate-free treatment strategy in RA. But it does suggest such a strategy will likely find a niche that’s restricted to patients with contraindications or intolerance to methotrexate, rather than a broader role in patients who are able to take methotrexate but don’t show adequate benefit without an add-on biologic, according to Dr. Dougados, professor of rheumatology at Cochin Hospital and René Descartes University, Paris.

The ACT-RAY trial introduced a more convoluted treatment protocol beginning at week 24. If at that point a patient had a DAS28 score in excess of 3.2, an open-label conventional disease-modifying antirheumatic drug other than methotrexate was added – for example, azathioprine, sulfasalazine, or hydroxychloroquine. This occurred in 29% of patients on the tocilizumab/methotrexate combination and in a similar 33% of those on tocilizumab/placebo.

Of note, the 52-week ACR 20, 50, 70, and 90 rates in the two study arms were similar. Nor were there significant differences between the two groups in terms of immunogenicity as reflected in rates of antidrug antibodies or neutralizing antidrug antibodies. And the incidence of elevated liver enzymes greater than three times the upper limit of normal was significantly lower in the methotrexate-free study arm.

"Despite some signals in favor of the add-on strategy – the percentage of patients in remission at week 52 and the structural data – this analysis suggests that tocilizumab monotherapy might be an acceptable therapeutic strategy in patients with a contraindication for or intolerance to methotrexate," he concluded.

Dr. Dougados reported serving as a consultant to Roche, which funds the ACT-RAY study.

BERLIN – The notion of a tocilizumab-based treatment strategy without the use of methotrexate in rheumatoid arthritis patients having an inadequate response to methotrexate monotherapy has lost some of its allure in light of 52-week data from the phase IIIb ACT-RAY trial.

Preliminary results of the randomized, double-blind study reported at last fall’s annual meeting of the American College of Rheumatology showed similar clinical improvement in patients with a prior inadequate response to methotrexate alone regardless of whether they received 24 weeks of methotrexate plus tocilizumab (Actemra) or tocilizumab plus placebo. But by the 52-week mark, things had changed, Dr. Maxime Dougados reported at the annual European Congress of Rheumatology.

At 52 weeks in the 556-patient trial, the DAS28 remission rate, defined as a DAS28 score below 2.6, had been achieved by 45.5% of patients assigned to methotrexate plus tocilizumab at 8 mg/kg given intravenously every 4 weeks, a significantly better outcome than the 36.6% rate in patients on the interleukin-6 inhibitor plus an oral placebo in lieu of methotrexate.

Moreover, while 92.4% of patients assigned to tocilizumab/methotrexate combination therapy were free of radiographic disease progression at 1 year, that was true for only 85.5% of those on tocilizumab plus placebo (P = .007).

This doesn’t mean the end for a tocilizumab-based, methotrexate-free treatment strategy in RA. But it does suggest such a strategy will likely find a niche that’s restricted to patients with contraindications or intolerance to methotrexate, rather than a broader role in patients who are able to take methotrexate but don’t show adequate benefit without an add-on biologic, according to Dr. Dougados, professor of rheumatology at Cochin Hospital and René Descartes University, Paris.

The ACT-RAY trial introduced a more convoluted treatment protocol beginning at week 24. If at that point a patient had a DAS28 score in excess of 3.2, an open-label conventional disease-modifying antirheumatic drug other than methotrexate was added – for example, azathioprine, sulfasalazine, or hydroxychloroquine. This occurred in 29% of patients on the tocilizumab/methotrexate combination and in a similar 33% of those on tocilizumab/placebo.

Of note, the 52-week ACR 20, 50, 70, and 90 rates in the two study arms were similar. Nor were there significant differences between the two groups in terms of immunogenicity as reflected in rates of antidrug antibodies or neutralizing antidrug antibodies. And the incidence of elevated liver enzymes greater than three times the upper limit of normal was significantly lower in the methotrexate-free study arm.

"Despite some signals in favor of the add-on strategy – the percentage of patients in remission at week 52 and the structural data – this analysis suggests that tocilizumab monotherapy might be an acceptable therapeutic strategy in patients with a contraindication for or intolerance to methotrexate," he concluded.

Dr. Dougados reported serving as a consultant to Roche, which funds the ACT-RAY study.

BERLIN – The notion of a tocilizumab-based treatment strategy without the use of methotrexate in rheumatoid arthritis patients having an inadequate response to methotrexate monotherapy has lost some of its allure in light of 52-week data from the phase IIIb ACT-RAY trial.

Preliminary results of the randomized, double-blind study reported at last fall’s annual meeting of the American College of Rheumatology showed similar clinical improvement in patients with a prior inadequate response to methotrexate alone regardless of whether they received 24 weeks of methotrexate plus tocilizumab (Actemra) or tocilizumab plus placebo. But by the 52-week mark, things had changed, Dr. Maxime Dougados reported at the annual European Congress of Rheumatology.

At 52 weeks in the 556-patient trial, the DAS28 remission rate, defined as a DAS28 score below 2.6, had been achieved by 45.5% of patients assigned to methotrexate plus tocilizumab at 8 mg/kg given intravenously every 4 weeks, a significantly better outcome than the 36.6% rate in patients on the interleukin-6 inhibitor plus an oral placebo in lieu of methotrexate.

Moreover, while 92.4% of patients assigned to tocilizumab/methotrexate combination therapy were free of radiographic disease progression at 1 year, that was true for only 85.5% of those on tocilizumab plus placebo (P = .007).

This doesn’t mean the end for a tocilizumab-based, methotrexate-free treatment strategy in RA. But it does suggest such a strategy will likely find a niche that’s restricted to patients with contraindications or intolerance to methotrexate, rather than a broader role in patients who are able to take methotrexate but don’t show adequate benefit without an add-on biologic, according to Dr. Dougados, professor of rheumatology at Cochin Hospital and René Descartes University, Paris.

The ACT-RAY trial introduced a more convoluted treatment protocol beginning at week 24. If at that point a patient had a DAS28 score in excess of 3.2, an open-label conventional disease-modifying antirheumatic drug other than methotrexate was added – for example, azathioprine, sulfasalazine, or hydroxychloroquine. This occurred in 29% of patients on the tocilizumab/methotrexate combination and in a similar 33% of those on tocilizumab/placebo.

Of note, the 52-week ACR 20, 50, 70, and 90 rates in the two study arms were similar. Nor were there significant differences between the two groups in terms of immunogenicity as reflected in rates of antidrug antibodies or neutralizing antidrug antibodies. And the incidence of elevated liver enzymes greater than three times the upper limit of normal was significantly lower in the methotrexate-free study arm.

"Despite some signals in favor of the add-on strategy – the percentage of patients in remission at week 52 and the structural data – this analysis suggests that tocilizumab monotherapy might be an acceptable therapeutic strategy in patients with a contraindication for or intolerance to methotrexate," he concluded.

Dr. Dougados reported serving as a consultant to Roche, which funds the ACT-RAY study.

BERLIN – Many of the classic manifestations of Behçet’s disease show a significant and previously unappreciated gender-based difference in expression, judging from the results of a new study of more than 10,000 patients.

For example, the most common form of skin involvement – erythema nodosum – is more common in women than men with Behçet’s disease, whereas papulopustular lesions and pseudofolliculitis occur more often in men with this highly variable multisystem disorder, Dr. Alfred Mahr reported at the annual European Congress of Rheumatology.

Dr. Mahr, chairman of the internal medicine department at Saint-Louis Hospital in Paris, presented a meta-analysis of the published literature on Behçet’s disease supplemented by new and unpublished data on 721 patients in the German Registry for Adamantiades-Behçet’s Disease for 1990-2011. All told, the analysis included 30 published studies, which, along with the unpublished data, comprised more than 10,000 affected patients.

The most common expression of Behçet’s disease was genital ulcers, affecting 79% of subjects, closely followed by skin involvement, at 77%. Erythema nodosum was present in 53% of patients, papulopustular skin lesions in 38%, and pseudofolliculitis in 29%.

Other frequent manifestations of Behçet’s disease included eye disease, affecting 49% of subjects, joint disease in 40%, major blood vessel involvement in 9.5%, and either deep vein or superficial thrombophlebitis in 31%.

Joint involvement was present in half of men with Behçet’s disease, compared with more than 60% of women. Even more striking was the gender difference in major vessel involvement, which affected roughly 30% of men and 10% of women. And cardiac involvement was documented in 14 men but just 1 woman.

These observations on gender differences in Behçet’s disease are important for two reasons, Dr. Mahr said: They may help in the differential diagnosis of this multisystem disorder, and they could shed light on disease pathogenesis. For example, Turkish investigators previously identified testosterone as having potentially relevant effects on neutrophil production (Clin. Exp. Rheumatol. 2007;25(4Suppl 45):46-51).

Dr. Mahr reported having no financial conflicts.

BERLIN – Many of the classic manifestations of Behçet’s disease show a significant and previously unappreciated gender-based difference in expression, judging from the results of a new study of more than 10,000 patients.

For example, the most common form of skin involvement – erythema nodosum – is more common in women than men with Behçet’s disease, whereas papulopustular lesions and pseudofolliculitis occur more often in men with this highly variable multisystem disorder, Dr. Alfred Mahr reported at the annual European Congress of Rheumatology.

Dr. Mahr, chairman of the internal medicine department at Saint-Louis Hospital in Paris, presented a meta-analysis of the published literature on Behçet’s disease supplemented by new and unpublished data on 721 patients in the German Registry for Adamantiades-Behçet’s Disease for 1990-2011. All told, the analysis included 30 published studies, which, along with the unpublished data, comprised more than 10,000 affected patients.

The most common expression of Behçet’s disease was genital ulcers, affecting 79% of subjects, closely followed by skin involvement, at 77%. Erythema nodosum was present in 53% of patients, papulopustular skin lesions in 38%, and pseudofolliculitis in 29%.

Other frequent manifestations of Behçet’s disease included eye disease, affecting 49% of subjects, joint disease in 40%, major blood vessel involvement in 9.5%, and either deep vein or superficial thrombophlebitis in 31%.

Joint involvement was present in half of men with Behçet’s disease, compared with more than 60% of women. Even more striking was the gender difference in major vessel involvement, which affected roughly 30% of men and 10% of women. And cardiac involvement was documented in 14 men but just 1 woman.

These observations on gender differences in Behçet’s disease are important for two reasons, Dr. Mahr said: They may help in the differential diagnosis of this multisystem disorder, and they could shed light on disease pathogenesis. For example, Turkish investigators previously identified testosterone as having potentially relevant effects on neutrophil production (Clin. Exp. Rheumatol. 2007;25(4Suppl 45):46-51).

Dr. Mahr reported having no financial conflicts.

BERLIN – Many of the classic manifestations of Behçet’s disease show a significant and previously unappreciated gender-based difference in expression, judging from the results of a new study of more than 10,000 patients.

For example, the most common form of skin involvement – erythema nodosum – is more common in women than men with Behçet’s disease, whereas papulopustular lesions and pseudofolliculitis occur more often in men with this highly variable multisystem disorder, Dr. Alfred Mahr reported at the annual European Congress of Rheumatology.

Dr. Mahr, chairman of the internal medicine department at Saint-Louis Hospital in Paris, presented a meta-analysis of the published literature on Behçet’s disease supplemented by new and unpublished data on 721 patients in the German Registry for Adamantiades-Behçet’s Disease for 1990-2011. All told, the analysis included 30 published studies, which, along with the unpublished data, comprised more than 10,000 affected patients.

The most common expression of Behçet’s disease was genital ulcers, affecting 79% of subjects, closely followed by skin involvement, at 77%. Erythema nodosum was present in 53% of patients, papulopustular skin lesions in 38%, and pseudofolliculitis in 29%.

Other frequent manifestations of Behçet’s disease included eye disease, affecting 49% of subjects, joint disease in 40%, major blood vessel involvement in 9.5%, and either deep vein or superficial thrombophlebitis in 31%.

Joint involvement was present in half of men with Behçet’s disease, compared with more than 60% of women. Even more striking was the gender difference in major vessel involvement, which affected roughly 30% of men and 10% of women. And cardiac involvement was documented in 14 men but just 1 woman.

These observations on gender differences in Behçet’s disease are important for two reasons, Dr. Mahr said: They may help in the differential diagnosis of this multisystem disorder, and they could shed light on disease pathogenesis. For example, Turkish investigators previously identified testosterone as having potentially relevant effects on neutrophil production (Clin. Exp. Rheumatol. 2007;25(4Suppl 45):46-51).

Dr. Mahr reported having no financial conflicts.

BERLIN – The interleukin-17 blocker ixekizumab demonstrated significant clinical benefit and noteworthy rapid onset of efficacy in a phase II clinical trial in rheumatoid arthritis patients.

The anti-IL-17 monoclonal antibody proved effective both in patients naive to biologic therapy and in prior inadequate responders to tumor necrosis factor (TNF) inhibitors, reported Dr. Mark Genovese, who is professor of medicine at Stanford (Calif.) University.

"We saw ACR 20 responses and DAS28 and C-reactive protein values decrease within 3 days," he observed.

The randomized, double-blind study included 260 biologic-naive subjects and 188 others with an inadequate response to one or more TNF inhibitors. The biologic-naive patients were randomized to subcutaneous ixekizumab at 3, 10, 30, 80, or 180 mg at weeks 0, 1, 2, and every 2 weeks thereafter or to placebo. The TNF inhibitor–refractory patients received ixekizumab at 80 or 180 mg or placebo on the same dosing schedule. Everyone also received methotrexate or another nonbiologic disease-modifying antirheumatic drug.

The prespecified primary end point required by the Food and Drug Administration was the ACR 20 response at week 12. Although all patients in the biologic-naive group had higher ACR 20 response rates than did the placebo-treated controls, there was no clear dose-response effect. Only in subjects on ixekizumab at 30 mg did the difference from placebo attain statistical significance; their ACR 20 rate of 70% was twice than in controls.

In patients with prior inadequate response to anti-TNF agents, both the 80- and 180-mg doses of the anti-IL-17 biologic resulted in ACR 20 response rates of about 40%, roughly twice the rate with placebo.

For the secondary end points of Disease Activity Score based on 28-joint counts (DAS28), Clinical Disease Activity Index, and C-reactive protein titers, moderate to good responses were seen at multiple doses. For example, mean CRP levels remained essentially unchanged over time in the placebo group but dropped by 10.2-11.0 mg/L from a baseline of about 20 mg/L in biologic-naive patients on 30, 80, or 180 mg of ixekizumab. Mean CRP dropped by 5.7 and 8.1 mg/L, respectively, in patients with prior inadequate response to anti-TNF therapy who were assigned to ixekizumab at 80 and 180 mg.

Asked later about the somewhat muddy ACR 20 findings, Dr. Genovese replied, "This isn’t the only trial to date that’s been able to show a much nicer dose-response curve with DAS28 as opposed to ACR 20. While it’s only my personal opinion, it appears to me that the DAS scoring system seems to be a more robust and clinically applicable scoring system for use in outcomes in a dose-response study."

Ixekizumab’s safety profile in the phase II study was "comparable to other biologic therapies," the rheumatologist continued. Attrition was low, with only three treatment discontinuations because of adverse events in the active-treatment arm. Serious treatment-emergent adverse events occurred in 1.7% of controls and 4% of patients on the IL-17 inhibitor. Upper respiratory and urinary tract infections were slightly more frequent in ixekizumab-treated patients; however, no mycobacterial or systemic fungal infections occurred. Neutrophil counts were modestly lower in the ixekizumab group but were unrelated to infection risk.

Dr. Genovese reported receiving research grants from and serving as a consultant to Eli Lilly, which is developing ixekizumab for treatment of rheumatoid arthritis and psoriasis.

BERLIN – The interleukin-17 blocker ixekizumab demonstrated significant clinical benefit and noteworthy rapid onset of efficacy in a phase II clinical trial in rheumatoid arthritis patients.

The anti-IL-17 monoclonal antibody proved effective both in patients naive to biologic therapy and in prior inadequate responders to tumor necrosis factor (TNF) inhibitors, reported Dr. Mark Genovese, who is professor of medicine at Stanford (Calif.) University.

"We saw ACR 20 responses and DAS28 and C-reactive protein values decrease within 3 days," he observed.

The randomized, double-blind study included 260 biologic-naive subjects and 188 others with an inadequate response to one or more TNF inhibitors. The biologic-naive patients were randomized to subcutaneous ixekizumab at 3, 10, 30, 80, or 180 mg at weeks 0, 1, 2, and every 2 weeks thereafter or to placebo. The TNF inhibitor–refractory patients received ixekizumab at 80 or 180 mg or placebo on the same dosing schedule. Everyone also received methotrexate or another nonbiologic disease-modifying antirheumatic drug.

The prespecified primary end point required by the Food and Drug Administration was the ACR 20 response at week 12. Although all patients in the biologic-naive group had higher ACR 20 response rates than did the placebo-treated controls, there was no clear dose-response effect. Only in subjects on ixekizumab at 30 mg did the difference from placebo attain statistical significance; their ACR 20 rate of 70% was twice than in controls.

In patients with prior inadequate response to anti-TNF agents, both the 80- and 180-mg doses of the anti-IL-17 biologic resulted in ACR 20 response rates of about 40%, roughly twice the rate with placebo.

For the secondary end points of Disease Activity Score based on 28-joint counts (DAS28), Clinical Disease Activity Index, and C-reactive protein titers, moderate to good responses were seen at multiple doses. For example, mean CRP levels remained essentially unchanged over time in the placebo group but dropped by 10.2-11.0 mg/L from a baseline of about 20 mg/L in biologic-naive patients on 30, 80, or 180 mg of ixekizumab. Mean CRP dropped by 5.7 and 8.1 mg/L, respectively, in patients with prior inadequate response to anti-TNF therapy who were assigned to ixekizumab at 80 and 180 mg.

Asked later about the somewhat muddy ACR 20 findings, Dr. Genovese replied, "This isn’t the only trial to date that’s been able to show a much nicer dose-response curve with DAS28 as opposed to ACR 20. While it’s only my personal opinion, it appears to me that the DAS scoring system seems to be a more robust and clinically applicable scoring system for use in outcomes in a dose-response study."

Ixekizumab’s safety profile in the phase II study was "comparable to other biologic therapies," the rheumatologist continued. Attrition was low, with only three treatment discontinuations because of adverse events in the active-treatment arm. Serious treatment-emergent adverse events occurred in 1.7% of controls and 4% of patients on the IL-17 inhibitor. Upper respiratory and urinary tract infections were slightly more frequent in ixekizumab-treated patients; however, no mycobacterial or systemic fungal infections occurred. Neutrophil counts were modestly lower in the ixekizumab group but were unrelated to infection risk.

Dr. Genovese reported receiving research grants from and serving as a consultant to Eli Lilly, which is developing ixekizumab for treatment of rheumatoid arthritis and psoriasis.

BERLIN – The interleukin-17 blocker ixekizumab demonstrated significant clinical benefit and noteworthy rapid onset of efficacy in a phase II clinical trial in rheumatoid arthritis patients.

The anti-IL-17 monoclonal antibody proved effective both in patients naive to biologic therapy and in prior inadequate responders to tumor necrosis factor (TNF) inhibitors, reported Dr. Mark Genovese, who is professor of medicine at Stanford (Calif.) University.

"We saw ACR 20 responses and DAS28 and C-reactive protein values decrease within 3 days," he observed.

The randomized, double-blind study included 260 biologic-naive subjects and 188 others with an inadequate response to one or more TNF inhibitors. The biologic-naive patients were randomized to subcutaneous ixekizumab at 3, 10, 30, 80, or 180 mg at weeks 0, 1, 2, and every 2 weeks thereafter or to placebo. The TNF inhibitor–refractory patients received ixekizumab at 80 or 180 mg or placebo on the same dosing schedule. Everyone also received methotrexate or another nonbiologic disease-modifying antirheumatic drug.

The prespecified primary end point required by the Food and Drug Administration was the ACR 20 response at week 12. Although all patients in the biologic-naive group had higher ACR 20 response rates than did the placebo-treated controls, there was no clear dose-response effect. Only in subjects on ixekizumab at 30 mg did the difference from placebo attain statistical significance; their ACR 20 rate of 70% was twice than in controls.

In patients with prior inadequate response to anti-TNF agents, both the 80- and 180-mg doses of the anti-IL-17 biologic resulted in ACR 20 response rates of about 40%, roughly twice the rate with placebo.

For the secondary end points of Disease Activity Score based on 28-joint counts (DAS28), Clinical Disease Activity Index, and C-reactive protein titers, moderate to good responses were seen at multiple doses. For example, mean CRP levels remained essentially unchanged over time in the placebo group but dropped by 10.2-11.0 mg/L from a baseline of about 20 mg/L in biologic-naive patients on 30, 80, or 180 mg of ixekizumab. Mean CRP dropped by 5.7 and 8.1 mg/L, respectively, in patients with prior inadequate response to anti-TNF therapy who were assigned to ixekizumab at 80 and 180 mg.

Asked later about the somewhat muddy ACR 20 findings, Dr. Genovese replied, "This isn’t the only trial to date that’s been able to show a much nicer dose-response curve with DAS28 as opposed to ACR 20. While it’s only my personal opinion, it appears to me that the DAS scoring system seems to be a more robust and clinically applicable scoring system for use in outcomes in a dose-response study."

Ixekizumab’s safety profile in the phase II study was "comparable to other biologic therapies," the rheumatologist continued. Attrition was low, with only three treatment discontinuations because of adverse events in the active-treatment arm. Serious treatment-emergent adverse events occurred in 1.7% of controls and 4% of patients on the IL-17 inhibitor. Upper respiratory and urinary tract infections were slightly more frequent in ixekizumab-treated patients; however, no mycobacterial or systemic fungal infections occurred. Neutrophil counts were modestly lower in the ixekizumab group but were unrelated to infection risk.

Dr. Genovese reported receiving research grants from and serving as a consultant to Eli Lilly, which is developing ixekizumab for treatment of rheumatoid arthritis and psoriasis.