ACR Annual Meeting 2011

CHICAGO – Combination induction therapy with adalimumab and methotrexate was superior to methotrexate alone for the treatment of patients with early rheumatoid arthritis in the randomized, controlled, multicenter HIT HARD trial.

The mean 28-joint count disease activity score (DAS28) was reduced from 6.2 to 3.0 after a 24-week induction phase in 87 RA patients randomized to receive combination therapy, which was significantly greater than the reduction from 6.3 to 3.5 in 85 patients randomized to receive methotrexate monotherapy for 24 weeks, according to Dr. Gerd R. Burmester reported at the annual meeting of the American College of Rheumatology.

After 24 weeks, adalimumab was withdrawn in the patients on combination therapy, and both groups received only methotrexate for an additional 24 weeks. The 48-week DAS28 – the primary end point of the double-blind study – remained numerically, but not significantly, lower in the group who initially received combination therapy, compared with the group who received initial monotherapy (3.2 vs. 3.4, respectively), said Dr. Burmester, professor of rheumatology at the Charité-Universitatsmedizin Berlin.

As with the primary outcome measure, the differences between the combination therapy and methotrexate monotherapy groups on secondary outcome measures, including remission (defined as DAS28 less than 2.6), ACR50 and ACR70 response rates (indicating 50% and 70% improvement in the signs and symptoms of disease), and functional status as measured by the Health Assessment Questionnaire (HAQ) differed significantly at week 24, but not at week 48.

For example, 47% vs. 31% of patients in the combination and monotherapy groups, respectively, achieved remission by week 24, but those percentages changed to 44% and 37% by week 48. Also, HAQ scores, which were 1.4 and 1.3 at baseline, were 0.49 vs. 0.72 at 24 weeks, compared with 0.60 and 0.65 at 48 weeks.

However, despite the lack of a significant difference in the DAS28 scores and the secondary outcome measures between the two groups at 48-week follow-up, there was a significant difference in regard to radiographic progression of disease: mean total van der Heijde/Sharp scores at that time were 6.3 and 11.4 in the groups, respectively, Dr. Burmester said. The extent to which this difference is clinically meaningful remains unclear, he noted.

Patients in the study had early RA with duration of no more than 1 year (with 87% having disease duration of 3 months or less) and had not been treated previously with disease-modifying antirheumatic drugs. All had active disease, swollen and tender joint counts of at least six, and C-reactive protein levels of at least 10 mg/L. Those in the combination therapy group received 15 mg/week of subcutaneous methotrexate plus 40 mg of adalimumab every other week; monotherapy patients received 15 mg/week of methotrexate plus placebo, and no new safety signals were detected during the course of the study.

The findings suggest that combination therapy with adalimumab and methotrexate is significantly superior to methotrexate alone for induction therapy in early RA. Combination therapy produces sustained benefits in regard to radiographic progression at 48 weeks, even when adalimumab is withdrawn at 24 weeks.

"The numerical increase in the clinical outcome parameters of the group on combination therapy, which became apparent at around 40 weeks following treatment initiation, may reflect the loss of response after removal of adalimumab and is a finding that requires additional study, Dr. Burmester noted.

In an unrelated study also presented at ACR 2011, Dr. Arthur F. Kavanaugh, professor of medicine, and director of the center for innovative therapy in the division of rheumatology, allergy, and immunology at the University of California at San Diego and his colleagues similarly found that patients on combination adalimumab and methotrexate who achieved stable low-disease activity were able to maintain that response following adalimumab withdrawal in the OPTIMA (Optimal Protocol for Methotrexate and Adalimumab Combination Therapy in Early RA) Trial. But they also found that those patients with a low HAQ score at baseline were more likely than were other patients to fare well after adalimumab withdrawal, a finding that suggests that those with higher scores might do better if combination therapy is continued.

Still, this question remains, according to Dr. Burmester: "Is it medically or economically justifiable to use this [combination] induction therapy, which rapidly leads to improvement, or should we just wait for the success of methotrexate later?"

Another question that warrants study is whether higher doses of methotrexate would be better, he said, adding, "But there is one very important message: Treat as early as possible."

This study was funded by the German Ministry of Science. Dr. Burmester disclosed financial and other relationships with Abbott, MSD, Pfizer, and UCB. Other study authors also disclosed relationships with these companies and several others, including Bristol-Myers Squibb, Horizon Pharma, Merck Pharma, Merck Serono, Nitec Pharma, Novartis, Roche, and Wyeth Pharmaceuticals.

CHICAGO – Combination induction therapy with adalimumab and methotrexate was superior to methotrexate alone for the treatment of patients with early rheumatoid arthritis in the randomized, controlled, multicenter HIT HARD trial.

The mean 28-joint count disease activity score (DAS28) was reduced from 6.2 to 3.0 after a 24-week induction phase in 87 RA patients randomized to receive combination therapy, which was significantly greater than the reduction from 6.3 to 3.5 in 85 patients randomized to receive methotrexate monotherapy for 24 weeks, according to Dr. Gerd R. Burmester reported at the annual meeting of the American College of Rheumatology.

After 24 weeks, adalimumab was withdrawn in the patients on combination therapy, and both groups received only methotrexate for an additional 24 weeks. The 48-week DAS28 – the primary end point of the double-blind study – remained numerically, but not significantly, lower in the group who initially received combination therapy, compared with the group who received initial monotherapy (3.2 vs. 3.4, respectively), said Dr. Burmester, professor of rheumatology at the Charité-Universitatsmedizin Berlin.

As with the primary outcome measure, the differences between the combination therapy and methotrexate monotherapy groups on secondary outcome measures, including remission (defined as DAS28 less than 2.6), ACR50 and ACR70 response rates (indicating 50% and 70% improvement in the signs and symptoms of disease), and functional status as measured by the Health Assessment Questionnaire (HAQ) differed significantly at week 24, but not at week 48.

For example, 47% vs. 31% of patients in the combination and monotherapy groups, respectively, achieved remission by week 24, but those percentages changed to 44% and 37% by week 48. Also, HAQ scores, which were 1.4 and 1.3 at baseline, were 0.49 vs. 0.72 at 24 weeks, compared with 0.60 and 0.65 at 48 weeks.

However, despite the lack of a significant difference in the DAS28 scores and the secondary outcome measures between the two groups at 48-week follow-up, there was a significant difference in regard to radiographic progression of disease: mean total van der Heijde/Sharp scores at that time were 6.3 and 11.4 in the groups, respectively, Dr. Burmester said. The extent to which this difference is clinically meaningful remains unclear, he noted.

Patients in the study had early RA with duration of no more than 1 year (with 87% having disease duration of 3 months or less) and had not been treated previously with disease-modifying antirheumatic drugs. All had active disease, swollen and tender joint counts of at least six, and C-reactive protein levels of at least 10 mg/L. Those in the combination therapy group received 15 mg/week of subcutaneous methotrexate plus 40 mg of adalimumab every other week; monotherapy patients received 15 mg/week of methotrexate plus placebo, and no new safety signals were detected during the course of the study.

The findings suggest that combination therapy with adalimumab and methotrexate is significantly superior to methotrexate alone for induction therapy in early RA. Combination therapy produces sustained benefits in regard to radiographic progression at 48 weeks, even when adalimumab is withdrawn at 24 weeks.

"The numerical increase in the clinical outcome parameters of the group on combination therapy, which became apparent at around 40 weeks following treatment initiation, may reflect the loss of response after removal of adalimumab and is a finding that requires additional study, Dr. Burmester noted.

In an unrelated study also presented at ACR 2011, Dr. Arthur F. Kavanaugh, professor of medicine, and director of the center for innovative therapy in the division of rheumatology, allergy, and immunology at the University of California at San Diego and his colleagues similarly found that patients on combination adalimumab and methotrexate who achieved stable low-disease activity were able to maintain that response following adalimumab withdrawal in the OPTIMA (Optimal Protocol for Methotrexate and Adalimumab Combination Therapy in Early RA) Trial. But they also found that those patients with a low HAQ score at baseline were more likely than were other patients to fare well after adalimumab withdrawal, a finding that suggests that those with higher scores might do better if combination therapy is continued.

Still, this question remains, according to Dr. Burmester: "Is it medically or economically justifiable to use this [combination] induction therapy, which rapidly leads to improvement, or should we just wait for the success of methotrexate later?"

Another question that warrants study is whether higher doses of methotrexate would be better, he said, adding, "But there is one very important message: Treat as early as possible."

This study was funded by the German Ministry of Science. Dr. Burmester disclosed financial and other relationships with Abbott, MSD, Pfizer, and UCB. Other study authors also disclosed relationships with these companies and several others, including Bristol-Myers Squibb, Horizon Pharma, Merck Pharma, Merck Serono, Nitec Pharma, Novartis, Roche, and Wyeth Pharmaceuticals.

CHICAGO – Combination induction therapy with adalimumab and methotrexate was superior to methotrexate alone for the treatment of patients with early rheumatoid arthritis in the randomized, controlled, multicenter HIT HARD trial.

The mean 28-joint count disease activity score (DAS28) was reduced from 6.2 to 3.0 after a 24-week induction phase in 87 RA patients randomized to receive combination therapy, which was significantly greater than the reduction from 6.3 to 3.5 in 85 patients randomized to receive methotrexate monotherapy for 24 weeks, according to Dr. Gerd R. Burmester reported at the annual meeting of the American College of Rheumatology.

After 24 weeks, adalimumab was withdrawn in the patients on combination therapy, and both groups received only methotrexate for an additional 24 weeks. The 48-week DAS28 – the primary end point of the double-blind study – remained numerically, but not significantly, lower in the group who initially received combination therapy, compared with the group who received initial monotherapy (3.2 vs. 3.4, respectively), said Dr. Burmester, professor of rheumatology at the Charité-Universitatsmedizin Berlin.

As with the primary outcome measure, the differences between the combination therapy and methotrexate monotherapy groups on secondary outcome measures, including remission (defined as DAS28 less than 2.6), ACR50 and ACR70 response rates (indicating 50% and 70% improvement in the signs and symptoms of disease), and functional status as measured by the Health Assessment Questionnaire (HAQ) differed significantly at week 24, but not at week 48.

For example, 47% vs. 31% of patients in the combination and monotherapy groups, respectively, achieved remission by week 24, but those percentages changed to 44% and 37% by week 48. Also, HAQ scores, which were 1.4 and 1.3 at baseline, were 0.49 vs. 0.72 at 24 weeks, compared with 0.60 and 0.65 at 48 weeks.

However, despite the lack of a significant difference in the DAS28 scores and the secondary outcome measures between the two groups at 48-week follow-up, there was a significant difference in regard to radiographic progression of disease: mean total van der Heijde/Sharp scores at that time were 6.3 and 11.4 in the groups, respectively, Dr. Burmester said. The extent to which this difference is clinically meaningful remains unclear, he noted.

Patients in the study had early RA with duration of no more than 1 year (with 87% having disease duration of 3 months or less) and had not been treated previously with disease-modifying antirheumatic drugs. All had active disease, swollen and tender joint counts of at least six, and C-reactive protein levels of at least 10 mg/L. Those in the combination therapy group received 15 mg/week of subcutaneous methotrexate plus 40 mg of adalimumab every other week; monotherapy patients received 15 mg/week of methotrexate plus placebo, and no new safety signals were detected during the course of the study.

The findings suggest that combination therapy with adalimumab and methotrexate is significantly superior to methotrexate alone for induction therapy in early RA. Combination therapy produces sustained benefits in regard to radiographic progression at 48 weeks, even when adalimumab is withdrawn at 24 weeks.

"The numerical increase in the clinical outcome parameters of the group on combination therapy, which became apparent at around 40 weeks following treatment initiation, may reflect the loss of response after removal of adalimumab and is a finding that requires additional study, Dr. Burmester noted.

In an unrelated study also presented at ACR 2011, Dr. Arthur F. Kavanaugh, professor of medicine, and director of the center for innovative therapy in the division of rheumatology, allergy, and immunology at the University of California at San Diego and his colleagues similarly found that patients on combination adalimumab and methotrexate who achieved stable low-disease activity were able to maintain that response following adalimumab withdrawal in the OPTIMA (Optimal Protocol for Methotrexate and Adalimumab Combination Therapy in Early RA) Trial. But they also found that those patients with a low HAQ score at baseline were more likely than were other patients to fare well after adalimumab withdrawal, a finding that suggests that those with higher scores might do better if combination therapy is continued.

Still, this question remains, according to Dr. Burmester: "Is it medically or economically justifiable to use this [combination] induction therapy, which rapidly leads to improvement, or should we just wait for the success of methotrexate later?"

Another question that warrants study is whether higher doses of methotrexate would be better, he said, adding, "But there is one very important message: Treat as early as possible."

This study was funded by the German Ministry of Science. Dr. Burmester disclosed financial and other relationships with Abbott, MSD, Pfizer, and UCB. Other study authors also disclosed relationships with these companies and several others, including Bristol-Myers Squibb, Horizon Pharma, Merck Pharma, Merck Serono, Nitec Pharma, Novartis, Roche, and Wyeth Pharmaceuticals.

CHICAGO – Most patients with early active rheumatoid arthritis who discontinued adalimumab after achieving stable low disease activity on 26 weeks of combination therapy with methotrexate and adalimumab maintained that response through week 78 of treatment in a randomized, double-blind, placebo-controlled trial.

However, more patients who remained on the combination therapy achieved high levels of disease control, based on measures such as American College of Rheumatology 70% response (ACR70) and disease activity score 28 (DAS28) less than 2.6, which suggests that certain patients will benefit from remaining on combination therapy, according to Dr. Arthur F. Kavanaugh, professor of medicine and director of the center for innovative therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.

"The billion dollar question: Can we predict which patients we could [withdraw from a tumor necrosis factor inhibitor] and have absolutely no penalty ... is there a predictor?" said Dr. Kavanaugh, in discussing the implications of the findings of OPTIMA (study of the Optimal Protocol for Methotrexate and Adalimumab combination therapy in early RA) at the annual meeting of the American College of Rheumatology.

After "intense analysis of all manner of baseline characteristics," the answer is that only a low baseline score on the Health Assessment Questionnaire (HAQ) was found to predict which patients would do better with adalimumab withdrawal vs. continuation on combined therapy based on a composite outcome of DAS28 less than 2.6 or Simplified Disease Activity Index (SDAI) score of 3.3 or less and Health Assessment Questionnaire score of less than 0.5 (odds ratio, 1.9), he said.

Study participants were 207 adults aged 18 years or older from the first phase of the study. All had early active severe disease and achieved stable low disease activity defined as a DAS28 less than 3.2 on combination therapy within 26 weeks. For the current phase of the study, the patients were rerandomized to continue combination therapy or to have adalimumab withdrawn for an additional 52 weeks.

The percentage of patients achieving ACR20 and ACR50 responses, indicating 20% and 50% improvements in the signs and symptoms of disease, was 94% and 80% in the patients in whom adalimumab was withdrawn, compared with 95% and 89% in those who continued on combination therapy. The differences between the groups on these outcomes measures were not statistically significant.

Baseline characteristics in the withdrawal and continued combination therapy groups were similar; mean RA duration in both groups was 3.9 months. DAS28 was 5.9 and 5.7 in the withdrawal and continued combination therapy groups, respectively. C-reactive protein levels were 28.4 and 23.5 mg/L, mean 68-joint tender joint counts were 25.5 and 23.3, mean 66-joint swollen joint counts were 16.4 and 15.4, and mean modified total van der Heijde/Sharp scores were 12.2 and 10.8.

No significant difference was seen between the groups in regard to changes in SDAI scores of 11 or less, or in SDAI scores of 3.3 or less. No differences were seen between the groups in regard to radiographic progression as measured by mean modified total van der Heijde/Sharp scores, or in regard to changes in functional status as measured by mean HAQ scores.

The percentage who achieved ACR70, however, was 65% in the adalimumab withdrawal group, compared with 77% in the continued combination therapy group. This difference was statistically significant.

Furthermore, 81% of patients in the withdrawal group achieved DAS28 of less than 3.2, compared with 91% of those in the continued combination therapy group (P = .04), and 66% vs. 86% of patients in the groups, respectively, achieved DAS28 of 2.6 or less (P = .001).

Other than HAQ scores, nothing predicted with any strength who would do well after adalimumab withdrawal – even in univariate analysis, Dr. Kavanaugh stressed.

Dr. Kavanaugh disclosed that he received consulting fees or other remuneration from Abbott Laboratories. Other study authors also disclosed financial relationships with Abbott Laboratories and other companies, including, Bristol-Myers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MSD, Pfizer, Roche Pharmaceuticals, and/or UCB Pharma.

CHICAGO – Most patients with early active rheumatoid arthritis who discontinued adalimumab after achieving stable low disease activity on 26 weeks of combination therapy with methotrexate and adalimumab maintained that response through week 78 of treatment in a randomized, double-blind, placebo-controlled trial.

However, more patients who remained on the combination therapy achieved high levels of disease control, based on measures such as American College of Rheumatology 70% response (ACR70) and disease activity score 28 (DAS28) less than 2.6, which suggests that certain patients will benefit from remaining on combination therapy, according to Dr. Arthur F. Kavanaugh, professor of medicine and director of the center for innovative therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.

"The billion dollar question: Can we predict which patients we could [withdraw from a tumor necrosis factor inhibitor] and have absolutely no penalty ... is there a predictor?" said Dr. Kavanaugh, in discussing the implications of the findings of OPTIMA (study of the Optimal Protocol for Methotrexate and Adalimumab combination therapy in early RA) at the annual meeting of the American College of Rheumatology.

After "intense analysis of all manner of baseline characteristics," the answer is that only a low baseline score on the Health Assessment Questionnaire (HAQ) was found to predict which patients would do better with adalimumab withdrawal vs. continuation on combined therapy based on a composite outcome of DAS28 less than 2.6 or Simplified Disease Activity Index (SDAI) score of 3.3 or less and Health Assessment Questionnaire score of less than 0.5 (odds ratio, 1.9), he said.

Study participants were 207 adults aged 18 years or older from the first phase of the study. All had early active severe disease and achieved stable low disease activity defined as a DAS28 less than 3.2 on combination therapy within 26 weeks. For the current phase of the study, the patients were rerandomized to continue combination therapy or to have adalimumab withdrawn for an additional 52 weeks.

The percentage of patients achieving ACR20 and ACR50 responses, indicating 20% and 50% improvements in the signs and symptoms of disease, was 94% and 80% in the patients in whom adalimumab was withdrawn, compared with 95% and 89% in those who continued on combination therapy. The differences between the groups on these outcomes measures were not statistically significant.

Baseline characteristics in the withdrawal and continued combination therapy groups were similar; mean RA duration in both groups was 3.9 months. DAS28 was 5.9 and 5.7 in the withdrawal and continued combination therapy groups, respectively. C-reactive protein levels were 28.4 and 23.5 mg/L, mean 68-joint tender joint counts were 25.5 and 23.3, mean 66-joint swollen joint counts were 16.4 and 15.4, and mean modified total van der Heijde/Sharp scores were 12.2 and 10.8.

No significant difference was seen between the groups in regard to changes in SDAI scores of 11 or less, or in SDAI scores of 3.3 or less. No differences were seen between the groups in regard to radiographic progression as measured by mean modified total van der Heijde/Sharp scores, or in regard to changes in functional status as measured by mean HAQ scores.

The percentage who achieved ACR70, however, was 65% in the adalimumab withdrawal group, compared with 77% in the continued combination therapy group. This difference was statistically significant.

Furthermore, 81% of patients in the withdrawal group achieved DAS28 of less than 3.2, compared with 91% of those in the continued combination therapy group (P = .04), and 66% vs. 86% of patients in the groups, respectively, achieved DAS28 of 2.6 or less (P = .001).

Other than HAQ scores, nothing predicted with any strength who would do well after adalimumab withdrawal – even in univariate analysis, Dr. Kavanaugh stressed.

Dr. Kavanaugh disclosed that he received consulting fees or other remuneration from Abbott Laboratories. Other study authors also disclosed financial relationships with Abbott Laboratories and other companies, including, Bristol-Myers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MSD, Pfizer, Roche Pharmaceuticals, and/or UCB Pharma.

CHICAGO – Most patients with early active rheumatoid arthritis who discontinued adalimumab after achieving stable low disease activity on 26 weeks of combination therapy with methotrexate and adalimumab maintained that response through week 78 of treatment in a randomized, double-blind, placebo-controlled trial.

However, more patients who remained on the combination therapy achieved high levels of disease control, based on measures such as American College of Rheumatology 70% response (ACR70) and disease activity score 28 (DAS28) less than 2.6, which suggests that certain patients will benefit from remaining on combination therapy, according to Dr. Arthur F. Kavanaugh, professor of medicine and director of the center for innovative therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.

"The billion dollar question: Can we predict which patients we could [withdraw from a tumor necrosis factor inhibitor] and have absolutely no penalty ... is there a predictor?" said Dr. Kavanaugh, in discussing the implications of the findings of OPTIMA (study of the Optimal Protocol for Methotrexate and Adalimumab combination therapy in early RA) at the annual meeting of the American College of Rheumatology.

After "intense analysis of all manner of baseline characteristics," the answer is that only a low baseline score on the Health Assessment Questionnaire (HAQ) was found to predict which patients would do better with adalimumab withdrawal vs. continuation on combined therapy based on a composite outcome of DAS28 less than 2.6 or Simplified Disease Activity Index (SDAI) score of 3.3 or less and Health Assessment Questionnaire score of less than 0.5 (odds ratio, 1.9), he said.

Study participants were 207 adults aged 18 years or older from the first phase of the study. All had early active severe disease and achieved stable low disease activity defined as a DAS28 less than 3.2 on combination therapy within 26 weeks. For the current phase of the study, the patients were rerandomized to continue combination therapy or to have adalimumab withdrawn for an additional 52 weeks.

The percentage of patients achieving ACR20 and ACR50 responses, indicating 20% and 50% improvements in the signs and symptoms of disease, was 94% and 80% in the patients in whom adalimumab was withdrawn, compared with 95% and 89% in those who continued on combination therapy. The differences between the groups on these outcomes measures were not statistically significant.

Baseline characteristics in the withdrawal and continued combination therapy groups were similar; mean RA duration in both groups was 3.9 months. DAS28 was 5.9 and 5.7 in the withdrawal and continued combination therapy groups, respectively. C-reactive protein levels were 28.4 and 23.5 mg/L, mean 68-joint tender joint counts were 25.5 and 23.3, mean 66-joint swollen joint counts were 16.4 and 15.4, and mean modified total van der Heijde/Sharp scores were 12.2 and 10.8.

No significant difference was seen between the groups in regard to changes in SDAI scores of 11 or less, or in SDAI scores of 3.3 or less. No differences were seen between the groups in regard to radiographic progression as measured by mean modified total van der Heijde/Sharp scores, or in regard to changes in functional status as measured by mean HAQ scores.

The percentage who achieved ACR70, however, was 65% in the adalimumab withdrawal group, compared with 77% in the continued combination therapy group. This difference was statistically significant.

Furthermore, 81% of patients in the withdrawal group achieved DAS28 of less than 3.2, compared with 91% of those in the continued combination therapy group (P = .04), and 66% vs. 86% of patients in the groups, respectively, achieved DAS28 of 2.6 or less (P = .001).

Other than HAQ scores, nothing predicted with any strength who would do well after adalimumab withdrawal – even in univariate analysis, Dr. Kavanaugh stressed.

Dr. Kavanaugh disclosed that he received consulting fees or other remuneration from Abbott Laboratories. Other study authors also disclosed financial relationships with Abbott Laboratories and other companies, including, Bristol-Myers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MSD, Pfizer, Roche Pharmaceuticals, and/or UCB Pharma.

CHICAGO – Tocilizumab remained highly effective with a favorable risk-benefit ratio after 2 years of continuous treatment in 61 patients with severe, refractory systemic juvenile idiopathic arthritis, according to findings from the ongoing phase III TENDER trial.

The proportion of the patients who achieved the efficacy end point of ACR Pediatric 70 and ACR Pedi 90 (indicating 70% and 90% improvement, respectively, in the signs and symptoms of disease on the American College of Rheumatology pediatric evaluation scale) at 104 weeks of treatment was 88% and 71%, respectively. Mean joint counts decreased over time as well, with 55% of the patients having zero active joints, and 31% achieving inactive disease status by 104 weeks, according to Dr. Fabrizio De Benedetti, who reported his findings at the annual meeting of the American College of Rheumatology.

Additionally, 60% of patients who were on oral corticosteroids at baseline were able to discontinue that treatment by 104 weeks, and among those who continued on oral corticosteroids, the mean dose decreased from 0.30 mg/kg per day at baseline to 0.04 mg/kg per day, said Dr. Benedetti of Ospedale Pedatrico Bambino Gesu in Rome.

Tocilizumab is an interleukin-6 receptor inhibitor, which was approved by the Food and Drug Administration in April for use in children aged 2 years and older with systemic juvenile idiopathic arthritis (sJIA). It is also approved for adults with rheumatoid arthritis. The drug was shown to be effective in children in the first of three parts of the 5-year multicenter TENDER trial; those 12-week results were reported at ACR 2010.

Of 75 patients who received tocilizumab during that first part of the trial, 71% achieved ACR Pedi 70 and 37% achieved ACR Pedi 90, 16% had zero active joints, and none of the patients achieved inactive disease status.

The effects of treatment improved or were maintained over time, Dr. Benedetti said.

For example, ACR Pedi 70 and ACR Pedi 90 were achieved in 87% and 63%, respectively, of 106 patients receiving tocilizumab at 52 weeks, and in 87% and 71% of 101 patients receiving tocilizumab at 78 weeks, he said.

In the patients on active treatment at 104 weeks, 47 serious adverse events occurred (in 35 patients); 15 of these were considered by the investigators to be remotely, possibly, or probably related to tocilizumab. Additionally, 22 serious infections were reported in 20 patients, with 8 of those considered to be related to tocilizumab. All but one infection (which resulted in death) resolved; in all, three deaths occurred in the patients treated for 104 weeks, and one of those (which was a case of suspected streptococcal sepsis) was possibly treatment related. The rates of serious adverse events, serious adverse events attributable to the study drug, and serious infections were not increased, compared with rates in the initial 12-week part of the trial, he said.

Patients included in the TENDER trial were children aged 2-17 years with active, refractory sJIA (defined as disease duration of 6 months or longer with inadequate response to previous NSAIDs and oral corticosteroids). For part 1 of the trial, participants were randomized 2:1 to receive tocilizumab treatment or placebo every 2 weeks for 12 weeks. Tocilizumab dosing was based on body weight (8 mg/kg for those weighing 30 kg or greater, and 12 mg/kg for those weighing less than 30 kg). All patients, including those who escaped to open-label treatment in part 1, also entered part 2, during which they received open-label tocilizumab to week 104.

Patients were allowed to continue on stable doses of NSAIDs and methotrexate, with oral corticosteroid tapering. The 104-week analysis included those patients who completed all 104 weeks of treatment; 32 of 112 patients had not yet reached that treatment duration at the data cutoff, and 20 patients had withdrawn because of safety concerns, insufficient therapeutic response, or other nonsafety reasons (including one who withdrew at 104 weeks, but who was included in the analysis).

The findings of part 2 of the TENDER trial indicate that the response to tocilizumab is sustained, with no significant change in the safety profile, during long-term treatment in patients with sJIA, Dr. Benedetti said.

Furthermore, responses are maintained across a wide variety of baseline disease characteristics, according to findings of a post hoc analysis reported separately at ACR 2011 by Dr. De Benedetti.

In that analysis, which was performed at 52 weeks, trends were seen in regard to improved response based on joint count at baseline, disease duration, patient age, oral corticosteroid dose, and methotrexate use, but the differences did not reach statistical significance for those or for a number of other characteristics, including region, fever status, C-reactive protein levels, and previous biologic treatment, he said.

The TENDER trial is sponsored by Roche, the maker of tocilizumab. Dr. Benedetti disclosed relationships with Abbott Laboratories, Bristol-Myer Squibb, Hoffmann-La Roche, Novartis, Novimmune, Pfizer, Roche, and SOBI.

CHICAGO – Tocilizumab remained highly effective with a favorable risk-benefit ratio after 2 years of continuous treatment in 61 patients with severe, refractory systemic juvenile idiopathic arthritis, according to findings from the ongoing phase III TENDER trial.

The proportion of the patients who achieved the efficacy end point of ACR Pediatric 70 and ACR Pedi 90 (indicating 70% and 90% improvement, respectively, in the signs and symptoms of disease on the American College of Rheumatology pediatric evaluation scale) at 104 weeks of treatment was 88% and 71%, respectively. Mean joint counts decreased over time as well, with 55% of the patients having zero active joints, and 31% achieving inactive disease status by 104 weeks, according to Dr. Fabrizio De Benedetti, who reported his findings at the annual meeting of the American College of Rheumatology.

Additionally, 60% of patients who were on oral corticosteroids at baseline were able to discontinue that treatment by 104 weeks, and among those who continued on oral corticosteroids, the mean dose decreased from 0.30 mg/kg per day at baseline to 0.04 mg/kg per day, said Dr. Benedetti of Ospedale Pedatrico Bambino Gesu in Rome.

Tocilizumab is an interleukin-6 receptor inhibitor, which was approved by the Food and Drug Administration in April for use in children aged 2 years and older with systemic juvenile idiopathic arthritis (sJIA). It is also approved for adults with rheumatoid arthritis. The drug was shown to be effective in children in the first of three parts of the 5-year multicenter TENDER trial; those 12-week results were reported at ACR 2010.

Of 75 patients who received tocilizumab during that first part of the trial, 71% achieved ACR Pedi 70 and 37% achieved ACR Pedi 90, 16% had zero active joints, and none of the patients achieved inactive disease status.

The effects of treatment improved or were maintained over time, Dr. Benedetti said.

For example, ACR Pedi 70 and ACR Pedi 90 were achieved in 87% and 63%, respectively, of 106 patients receiving tocilizumab at 52 weeks, and in 87% and 71% of 101 patients receiving tocilizumab at 78 weeks, he said.

In the patients on active treatment at 104 weeks, 47 serious adverse events occurred (in 35 patients); 15 of these were considered by the investigators to be remotely, possibly, or probably related to tocilizumab. Additionally, 22 serious infections were reported in 20 patients, with 8 of those considered to be related to tocilizumab. All but one infection (which resulted in death) resolved; in all, three deaths occurred in the patients treated for 104 weeks, and one of those (which was a case of suspected streptococcal sepsis) was possibly treatment related. The rates of serious adverse events, serious adverse events attributable to the study drug, and serious infections were not increased, compared with rates in the initial 12-week part of the trial, he said.

Patients included in the TENDER trial were children aged 2-17 years with active, refractory sJIA (defined as disease duration of 6 months or longer with inadequate response to previous NSAIDs and oral corticosteroids). For part 1 of the trial, participants were randomized 2:1 to receive tocilizumab treatment or placebo every 2 weeks for 12 weeks. Tocilizumab dosing was based on body weight (8 mg/kg for those weighing 30 kg or greater, and 12 mg/kg for those weighing less than 30 kg). All patients, including those who escaped to open-label treatment in part 1, also entered part 2, during which they received open-label tocilizumab to week 104.

Patients were allowed to continue on stable doses of NSAIDs and methotrexate, with oral corticosteroid tapering. The 104-week analysis included those patients who completed all 104 weeks of treatment; 32 of 112 patients had not yet reached that treatment duration at the data cutoff, and 20 patients had withdrawn because of safety concerns, insufficient therapeutic response, or other nonsafety reasons (including one who withdrew at 104 weeks, but who was included in the analysis).

The findings of part 2 of the TENDER trial indicate that the response to tocilizumab is sustained, with no significant change in the safety profile, during long-term treatment in patients with sJIA, Dr. Benedetti said.

Furthermore, responses are maintained across a wide variety of baseline disease characteristics, according to findings of a post hoc analysis reported separately at ACR 2011 by Dr. De Benedetti.

In that analysis, which was performed at 52 weeks, trends were seen in regard to improved response based on joint count at baseline, disease duration, patient age, oral corticosteroid dose, and methotrexate use, but the differences did not reach statistical significance for those or for a number of other characteristics, including region, fever status, C-reactive protein levels, and previous biologic treatment, he said.

The TENDER trial is sponsored by Roche, the maker of tocilizumab. Dr. Benedetti disclosed relationships with Abbott Laboratories, Bristol-Myer Squibb, Hoffmann-La Roche, Novartis, Novimmune, Pfizer, Roche, and SOBI.

CHICAGO – Tocilizumab remained highly effective with a favorable risk-benefit ratio after 2 years of continuous treatment in 61 patients with severe, refractory systemic juvenile idiopathic arthritis, according to findings from the ongoing phase III TENDER trial.

The proportion of the patients who achieved the efficacy end point of ACR Pediatric 70 and ACR Pedi 90 (indicating 70% and 90% improvement, respectively, in the signs and symptoms of disease on the American College of Rheumatology pediatric evaluation scale) at 104 weeks of treatment was 88% and 71%, respectively. Mean joint counts decreased over time as well, with 55% of the patients having zero active joints, and 31% achieving inactive disease status by 104 weeks, according to Dr. Fabrizio De Benedetti, who reported his findings at the annual meeting of the American College of Rheumatology.

Additionally, 60% of patients who were on oral corticosteroids at baseline were able to discontinue that treatment by 104 weeks, and among those who continued on oral corticosteroids, the mean dose decreased from 0.30 mg/kg per day at baseline to 0.04 mg/kg per day, said Dr. Benedetti of Ospedale Pedatrico Bambino Gesu in Rome.

Tocilizumab is an interleukin-6 receptor inhibitor, which was approved by the Food and Drug Administration in April for use in children aged 2 years and older with systemic juvenile idiopathic arthritis (sJIA). It is also approved for adults with rheumatoid arthritis. The drug was shown to be effective in children in the first of three parts of the 5-year multicenter TENDER trial; those 12-week results were reported at ACR 2010.

Of 75 patients who received tocilizumab during that first part of the trial, 71% achieved ACR Pedi 70 and 37% achieved ACR Pedi 90, 16% had zero active joints, and none of the patients achieved inactive disease status.

The effects of treatment improved or were maintained over time, Dr. Benedetti said.

For example, ACR Pedi 70 and ACR Pedi 90 were achieved in 87% and 63%, respectively, of 106 patients receiving tocilizumab at 52 weeks, and in 87% and 71% of 101 patients receiving tocilizumab at 78 weeks, he said.

In the patients on active treatment at 104 weeks, 47 serious adverse events occurred (in 35 patients); 15 of these were considered by the investigators to be remotely, possibly, or probably related to tocilizumab. Additionally, 22 serious infections were reported in 20 patients, with 8 of those considered to be related to tocilizumab. All but one infection (which resulted in death) resolved; in all, three deaths occurred in the patients treated for 104 weeks, and one of those (which was a case of suspected streptococcal sepsis) was possibly treatment related. The rates of serious adverse events, serious adverse events attributable to the study drug, and serious infections were not increased, compared with rates in the initial 12-week part of the trial, he said.

Patients included in the TENDER trial were children aged 2-17 years with active, refractory sJIA (defined as disease duration of 6 months or longer with inadequate response to previous NSAIDs and oral corticosteroids). For part 1 of the trial, participants were randomized 2:1 to receive tocilizumab treatment or placebo every 2 weeks for 12 weeks. Tocilizumab dosing was based on body weight (8 mg/kg for those weighing 30 kg or greater, and 12 mg/kg for those weighing less than 30 kg). All patients, including those who escaped to open-label treatment in part 1, also entered part 2, during which they received open-label tocilizumab to week 104.

Patients were allowed to continue on stable doses of NSAIDs and methotrexate, with oral corticosteroid tapering. The 104-week analysis included those patients who completed all 104 weeks of treatment; 32 of 112 patients had not yet reached that treatment duration at the data cutoff, and 20 patients had withdrawn because of safety concerns, insufficient therapeutic response, or other nonsafety reasons (including one who withdrew at 104 weeks, but who was included in the analysis).

The findings of part 2 of the TENDER trial indicate that the response to tocilizumab is sustained, with no significant change in the safety profile, during long-term treatment in patients with sJIA, Dr. Benedetti said.

Furthermore, responses are maintained across a wide variety of baseline disease characteristics, according to findings of a post hoc analysis reported separately at ACR 2011 by Dr. De Benedetti.

In that analysis, which was performed at 52 weeks, trends were seen in regard to improved response based on joint count at baseline, disease duration, patient age, oral corticosteroid dose, and methotrexate use, but the differences did not reach statistical significance for those or for a number of other characteristics, including region, fever status, C-reactive protein levels, and previous biologic treatment, he said.

The TENDER trial is sponsored by Roche, the maker of tocilizumab. Dr. Benedetti disclosed relationships with Abbott Laboratories, Bristol-Myer Squibb, Hoffmann-La Roche, Novartis, Novimmune, Pfizer, Roche, and SOBI.

CHICAGO – The shingles vaccine does not increase the risk of shingles in patients taking biologics for autoimmune or inflammatory conditions, based on data from more than 7,000 adults. The findings were presented at the annual meeting of the American College of Rheumatology.

The findings suggest that the current recommendations that biologics users avoid live virus vaccines may be overly cautious, said Dr. Jeffrey R. Curtis of the University of Alabama, Birmingham.

The shingles vaccine (Zostavax) is recommended to protect older adults against herpes zoster, Dr. Curtis said, but concerns have been raised that reactivation of the live virus after vaccination for patients taking immunosuppressive medications might increase their risk of a shingles eruption.

To determine the risk of shingles in a population taking immunosuppressive medication, Dr. Curtis and his colleagues reviewed Medicare data from 2006 to 2009. They identified 7,781 adults aged 60 years and older who had rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease, and who had received a shingles vaccine while taking medication including biologics, disease modifying antirheumatic drugs (DMARDs), and oral glucocorticoids. The mean age of the study population was 74 years, most were white women, and none had any evidence of shingles infection at baseline.

Overall, the incidence rate for shingles at least 42 days after vaccination was 8 cases/1,000 person-years among vaccinated adults, compared with 12 cases/1,000 person-years in a cohort of unvaccinated adults.

In a subset of 636 vaccinated adults who were taking biologics (regardless of concomitant DMARDs or oral glucocorticoids), no cases of shingles were reported within the first 42 days after vaccination, Dr. Curtis emphasized. In fact, vaccination was associated with a decrease in herpes zoster incidence of approximately 30%, he added. By contrast, the incidence rate of shingles in unvaccinated patients taking biologics was 16 per 1,000 person-years. The incidence of infection was not significantly different in vaccinated patients taking biologics than in vaccinated patients taking non-biologic DMARDs, Dr. Curtis added.

The study was limited by the lack of information about the disease severity, Dr. Curtis noted. But the findings support the safety and effectiveness of the shingles vaccine for biologics users.

There are persistent unmet vaccination needs for patients with diseases that require immunosuppressive therapy, said Dr. Curtis. "A controlled safety trial of the zoster vaccine in biologic users may be indicated to further demonstrate its safety and effectiveness in preventing zoster infection," he said.

The study was supported by the Agency for Healthcare Research and Quality and the National Institutes of Health. Dr. Curtis has received research grants and consulting fees from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, Merck, Roche, and UCB.

CHICAGO – The shingles vaccine does not increase the risk of shingles in patients taking biologics for autoimmune or inflammatory conditions, based on data from more than 7,000 adults. The findings were presented at the annual meeting of the American College of Rheumatology.

The findings suggest that the current recommendations that biologics users avoid live virus vaccines may be overly cautious, said Dr. Jeffrey R. Curtis of the University of Alabama, Birmingham.

The shingles vaccine (Zostavax) is recommended to protect older adults against herpes zoster, Dr. Curtis said, but concerns have been raised that reactivation of the live virus after vaccination for patients taking immunosuppressive medications might increase their risk of a shingles eruption.

To determine the risk of shingles in a population taking immunosuppressive medication, Dr. Curtis and his colleagues reviewed Medicare data from 2006 to 2009. They identified 7,781 adults aged 60 years and older who had rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease, and who had received a shingles vaccine while taking medication including biologics, disease modifying antirheumatic drugs (DMARDs), and oral glucocorticoids. The mean age of the study population was 74 years, most were white women, and none had any evidence of shingles infection at baseline.

Overall, the incidence rate for shingles at least 42 days after vaccination was 8 cases/1,000 person-years among vaccinated adults, compared with 12 cases/1,000 person-years in a cohort of unvaccinated adults.

In a subset of 636 vaccinated adults who were taking biologics (regardless of concomitant DMARDs or oral glucocorticoids), no cases of shingles were reported within the first 42 days after vaccination, Dr. Curtis emphasized. In fact, vaccination was associated with a decrease in herpes zoster incidence of approximately 30%, he added. By contrast, the incidence rate of shingles in unvaccinated patients taking biologics was 16 per 1,000 person-years. The incidence of infection was not significantly different in vaccinated patients taking biologics than in vaccinated patients taking non-biologic DMARDs, Dr. Curtis added.

The study was limited by the lack of information about the disease severity, Dr. Curtis noted. But the findings support the safety and effectiveness of the shingles vaccine for biologics users.

There are persistent unmet vaccination needs for patients with diseases that require immunosuppressive therapy, said Dr. Curtis. "A controlled safety trial of the zoster vaccine in biologic users may be indicated to further demonstrate its safety and effectiveness in preventing zoster infection," he said.

The study was supported by the Agency for Healthcare Research and Quality and the National Institutes of Health. Dr. Curtis has received research grants and consulting fees from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, Merck, Roche, and UCB.

CHICAGO – The shingles vaccine does not increase the risk of shingles in patients taking biologics for autoimmune or inflammatory conditions, based on data from more than 7,000 adults. The findings were presented at the annual meeting of the American College of Rheumatology.

The findings suggest that the current recommendations that biologics users avoid live virus vaccines may be overly cautious, said Dr. Jeffrey R. Curtis of the University of Alabama, Birmingham.

The shingles vaccine (Zostavax) is recommended to protect older adults against herpes zoster, Dr. Curtis said, but concerns have been raised that reactivation of the live virus after vaccination for patients taking immunosuppressive medications might increase their risk of a shingles eruption.

To determine the risk of shingles in a population taking immunosuppressive medication, Dr. Curtis and his colleagues reviewed Medicare data from 2006 to 2009. They identified 7,781 adults aged 60 years and older who had rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease, and who had received a shingles vaccine while taking medication including biologics, disease modifying antirheumatic drugs (DMARDs), and oral glucocorticoids. The mean age of the study population was 74 years, most were white women, and none had any evidence of shingles infection at baseline.

Overall, the incidence rate for shingles at least 42 days after vaccination was 8 cases/1,000 person-years among vaccinated adults, compared with 12 cases/1,000 person-years in a cohort of unvaccinated adults.

In a subset of 636 vaccinated adults who were taking biologics (regardless of concomitant DMARDs or oral glucocorticoids), no cases of shingles were reported within the first 42 days after vaccination, Dr. Curtis emphasized. In fact, vaccination was associated with a decrease in herpes zoster incidence of approximately 30%, he added. By contrast, the incidence rate of shingles in unvaccinated patients taking biologics was 16 per 1,000 person-years. The incidence of infection was not significantly different in vaccinated patients taking biologics than in vaccinated patients taking non-biologic DMARDs, Dr. Curtis added.

The study was limited by the lack of information about the disease severity, Dr. Curtis noted. But the findings support the safety and effectiveness of the shingles vaccine for biologics users.

There are persistent unmet vaccination needs for patients with diseases that require immunosuppressive therapy, said Dr. Curtis. "A controlled safety trial of the zoster vaccine in biologic users may be indicated to further demonstrate its safety and effectiveness in preventing zoster infection," he said.

The study was supported by the Agency for Healthcare Research and Quality and the National Institutes of Health. Dr. Curtis has received research grants and consulting fees from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, Merck, Roche, and UCB.

CHICAGO – Methotrexate monotherapy is recommended and widely prescribed as the initial treatment approach for patients presenting with early rheumatoid arthritis, and now results of the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) Trial appear to validate the approach.

Findings from the randomized, double-blind 2-year trial involving 755 patients with early rheumatoid arthritis (RA) and a poor prognosis demonstrate that about 30% of those randomized to receive initial methotrexate monotherapy respond adequately and don’t need to step up to combination therapy. In addition, data from the study demonstrated that those who require step-up therapy because of inadequate response to methotrexate monotherapy do just as well radiographically as do those who receive combination therapy at the outset, according to Dr. James R. O’Dell, the Larson Professor of Medicine of the University of Nebraska and chief of rheumatology at the Veterans Affairs Medical Center, both in Omaha, and his colleagues reported at the annual meeting of the American College of Rheumatology.

"So there is no radiographic penalty for waiting to make that decision [to use combination therapy] clinically," said Dr. O’Dell, the new president of the American College of Rheumatology.

Patients in the TEAR Trial had active disease with a mean disease duration of 3.6 months and a mean disease activity 28 (DAS28) score of 5.8, had not received prior disease-modifying antirheumatic drug (DMARD) therapy, and had a poor prognosis based on the findings of rheumatoid factor positivity, a positive cyclic citrullinated peptide antibody test, or the presence of at least two erosions. They were randomized 2:1 to receive methotrexate monotherapy or combination therapy (either methotrexate plus etanercept or methotrexate plus sulfasalazine and hydroxychloroquine).

Methotrexate monotherapy patients who failed to achieve DAS28 of less than 3.2 within 24 weeks switched to one of the combinations.

Of 379 patients who received methotrexate monotherapy, 28% achieved a DAS28 below 3.2. Those who remained on monotherapy at week 102 had a mean DAS28 of 2.7, which both indicated durability of response and was nominally lower than the mean DAS28 of 3.0 in the initial combination therapy patients, Dr. O’Dell said.

Radiographic progression in the methotrexate monotherapy patients, compared with the immediate combination therapy patients was also nominally – and reassuringly – better (total sharp scores of 0.1 and 1.1, respectively), he noted. In addition, DAS28 scores as well as measures of radiographic progression were comparable in the step-up patients and the immediate combination patients beginning at 12 weeks after step-up through 102 weeks.

As for baseline differences between the patients on methotrexate monotherapy who did and did not require step-up therapy, those on step-up were more likely to be female and to have a higher DAS28 and an elevated body mass index.

"None of these differences were statistically significant, but one wonders about the overall accumulative effect of those factors on predicting response," Dr. O’Dell said.

Although methotrexate monotherapy is widely accepted as the appropriate approach to treatment in early RA patients and is recommended by both the ACR and the European League Against Rheumatism, this is the first blinded randomized trial to validate this approach, he noted.

Dr. O’Dell disclosed that he received grant money for the National Institutes of Health and the Department of Veterans Affairs. Other authors disclosed relationships with Abbott, American Shoulder and Elbow, Amgen, which provided grant money for the study, as well as BMS, Centacor, Corona, Crescendo, Genentech, Ortho Biotech Services, Pfizer, Roche, Teva Pharmaceuticals, and/or UCB.

CHICAGO – Methotrexate monotherapy is recommended and widely prescribed as the initial treatment approach for patients presenting with early rheumatoid arthritis, and now results of the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) Trial appear to validate the approach.

Findings from the randomized, double-blind 2-year trial involving 755 patients with early rheumatoid arthritis (RA) and a poor prognosis demonstrate that about 30% of those randomized to receive initial methotrexate monotherapy respond adequately and don’t need to step up to combination therapy. In addition, data from the study demonstrated that those who require step-up therapy because of inadequate response to methotrexate monotherapy do just as well radiographically as do those who receive combination therapy at the outset, according to Dr. James R. O’Dell, the Larson Professor of Medicine of the University of Nebraska and chief of rheumatology at the Veterans Affairs Medical Center, both in Omaha, and his colleagues reported at the annual meeting of the American College of Rheumatology.

"So there is no radiographic penalty for waiting to make that decision [to use combination therapy] clinically," said Dr. O’Dell, the new president of the American College of Rheumatology.

Patients in the TEAR Trial had active disease with a mean disease duration of 3.6 months and a mean disease activity 28 (DAS28) score of 5.8, had not received prior disease-modifying antirheumatic drug (DMARD) therapy, and had a poor prognosis based on the findings of rheumatoid factor positivity, a positive cyclic citrullinated peptide antibody test, or the presence of at least two erosions. They were randomized 2:1 to receive methotrexate monotherapy or combination therapy (either methotrexate plus etanercept or methotrexate plus sulfasalazine and hydroxychloroquine).

Methotrexate monotherapy patients who failed to achieve DAS28 of less than 3.2 within 24 weeks switched to one of the combinations.

Of 379 patients who received methotrexate monotherapy, 28% achieved a DAS28 below 3.2. Those who remained on monotherapy at week 102 had a mean DAS28 of 2.7, which both indicated durability of response and was nominally lower than the mean DAS28 of 3.0 in the initial combination therapy patients, Dr. O’Dell said.

Radiographic progression in the methotrexate monotherapy patients, compared with the immediate combination therapy patients was also nominally – and reassuringly – better (total sharp scores of 0.1 and 1.1, respectively), he noted. In addition, DAS28 scores as well as measures of radiographic progression were comparable in the step-up patients and the immediate combination patients beginning at 12 weeks after step-up through 102 weeks.

As for baseline differences between the patients on methotrexate monotherapy who did and did not require step-up therapy, those on step-up were more likely to be female and to have a higher DAS28 and an elevated body mass index.

"None of these differences were statistically significant, but one wonders about the overall accumulative effect of those factors on predicting response," Dr. O’Dell said.

Although methotrexate monotherapy is widely accepted as the appropriate approach to treatment in early RA patients and is recommended by both the ACR and the European League Against Rheumatism, this is the first blinded randomized trial to validate this approach, he noted.

Dr. O’Dell disclosed that he received grant money for the National Institutes of Health and the Department of Veterans Affairs. Other authors disclosed relationships with Abbott, American Shoulder and Elbow, Amgen, which provided grant money for the study, as well as BMS, Centacor, Corona, Crescendo, Genentech, Ortho Biotech Services, Pfizer, Roche, Teva Pharmaceuticals, and/or UCB.

CHICAGO – Methotrexate monotherapy is recommended and widely prescribed as the initial treatment approach for patients presenting with early rheumatoid arthritis, and now results of the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) Trial appear to validate the approach.

Findings from the randomized, double-blind 2-year trial involving 755 patients with early rheumatoid arthritis (RA) and a poor prognosis demonstrate that about 30% of those randomized to receive initial methotrexate monotherapy respond adequately and don’t need to step up to combination therapy. In addition, data from the study demonstrated that those who require step-up therapy because of inadequate response to methotrexate monotherapy do just as well radiographically as do those who receive combination therapy at the outset, according to Dr. James R. O’Dell, the Larson Professor of Medicine of the University of Nebraska and chief of rheumatology at the Veterans Affairs Medical Center, both in Omaha, and his colleagues reported at the annual meeting of the American College of Rheumatology.

"So there is no radiographic penalty for waiting to make that decision [to use combination therapy] clinically," said Dr. O’Dell, the new president of the American College of Rheumatology.

Patients in the TEAR Trial had active disease with a mean disease duration of 3.6 months and a mean disease activity 28 (DAS28) score of 5.8, had not received prior disease-modifying antirheumatic drug (DMARD) therapy, and had a poor prognosis based on the findings of rheumatoid factor positivity, a positive cyclic citrullinated peptide antibody test, or the presence of at least two erosions. They were randomized 2:1 to receive methotrexate monotherapy or combination therapy (either methotrexate plus etanercept or methotrexate plus sulfasalazine and hydroxychloroquine).

Methotrexate monotherapy patients who failed to achieve DAS28 of less than 3.2 within 24 weeks switched to one of the combinations.

Of 379 patients who received methotrexate monotherapy, 28% achieved a DAS28 below 3.2. Those who remained on monotherapy at week 102 had a mean DAS28 of 2.7, which both indicated durability of response and was nominally lower than the mean DAS28 of 3.0 in the initial combination therapy patients, Dr. O’Dell said.

Radiographic progression in the methotrexate monotherapy patients, compared with the immediate combination therapy patients was also nominally – and reassuringly – better (total sharp scores of 0.1 and 1.1, respectively), he noted. In addition, DAS28 scores as well as measures of radiographic progression were comparable in the step-up patients and the immediate combination patients beginning at 12 weeks after step-up through 102 weeks.

As for baseline differences between the patients on methotrexate monotherapy who did and did not require step-up therapy, those on step-up were more likely to be female and to have a higher DAS28 and an elevated body mass index.

"None of these differences were statistically significant, but one wonders about the overall accumulative effect of those factors on predicting response," Dr. O’Dell said.

Although methotrexate monotherapy is widely accepted as the appropriate approach to treatment in early RA patients and is recommended by both the ACR and the European League Against Rheumatism, this is the first blinded randomized trial to validate this approach, he noted.

Dr. O’Dell disclosed that he received grant money for the National Institutes of Health and the Department of Veterans Affairs. Other authors disclosed relationships with Abbott, American Shoulder and Elbow, Amgen, which provided grant money for the study, as well as BMS, Centacor, Corona, Crescendo, Genentech, Ortho Biotech Services, Pfizer, Roche, Teva Pharmaceuticals, and/or UCB.

CHICAGO – Denosumab remained well-tolerated, safe, and effective for maintaining reduced bone turnover and for increasing bone mineral density after 6 years of continuous use in 2,343 postmenopausal women with increased fracture risk due to osteoporosis.

These findings come from the first 3 years of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis) extension trial.

The fully human monoclonal antibody also led to significant gains in bone mineral density in a "crossover" group of 2,207 women who received placebo during the original FREEDOM trial – a pivotal trial published in 2009 that demonstrated a favorable risk/benefit profile for denosumab (N. Engl. J. Med. 2009;361:756-65).

The agent subsequently received Food and Drug Administration approval for the treatment of postmenopausal women with osteoporosis and an increased fracture risk.

The annual incidences of new vertebral and nonvertebral fractures were lower in the crossover group in the extension trial than in the FREEDOM placebo group.

During the open-label active treatment extension trial, which was designed to investigate the efficacy and safety of the drug for up to 10 years, participants received 60 mg of denosumab as a subcutaneous injection every 6 months along with daily supplemental calcium and vitamin D. In the first 3 years of the extension trial, those in the long-term treatment group experienced additional, statistically significant increases in bone mineral density (cumulative 6-year gains of 15.2% at the lumbar spine and 7.5% at the total hip), and those in the crossover group experienced significant mean gains in bone mineral density that were similar to those seen initially in the FREEDOM trial active treatment group (9.4% at the lumbar spine and 4.8% at the total hip), Dr. Jacques P. Brown reported during a late-breaking abstract session at the annual meeting of the American College of Rheumatology.

The gains seen in the active treatment group in the FREEDOM trial at 3 years were 10.1% at the lumbar spine and 5.7% at the total hip, said Dr. Brown of Laval University, Quebec City.

Measures of serum carboxy-terminal telopeptide (CTX), which is a marker of bone resorption, demonstrated "a profound reduction in bone resorption" appearing rapidly and similarly after the first treatment in the cross-over group, and after the seventh treatment in the long-term treatment group – with the "characteristic attenuation observed at the end of the dosing period," Dr. Brown said.

The annual incidences of new vertebral and nonvertebral fractures were lower in the crossover group in the extension trial than in the FREEDOM placebo group. Fracture incidence also remained low in the long-term group in the extension trial, he said, noting that adverse events and serious adverse events also did not increase over time in the extension trial, and there were no "significant imbalances between the groups."

Osteonecrosis of the jaw occurred in two patients in both the long-term and crossover treatment groups; in the crossover group, both cases resolved completely within the follow-up period, and one of those patients had continued on treatment. The cases in the long-term treatment group remained unresolved at the time of Dr. Brown’s report.

These interim findings from the FREEDOM extension trial demonstrate that denosumab treatment for up to 6 years lead to continued improvement in women on long-term treatment, and that treatment for up to 3 years in the crossover group largely reproduced the observations in the original FREEDOM denosumab group, Dr. Brown concluded.

Dr. Brown disclosed having various relationships with Abbott, Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Servier, and Warner Chilcott. Other authors on the study also disclosed various relationships with these and/or other pharmaceutical companies.

CHICAGO – Denosumab remained well-tolerated, safe, and effective for maintaining reduced bone turnover and for increasing bone mineral density after 6 years of continuous use in 2,343 postmenopausal women with increased fracture risk due to osteoporosis.

These findings come from the first 3 years of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis) extension trial.

The fully human monoclonal antibody also led to significant gains in bone mineral density in a "crossover" group of 2,207 women who received placebo during the original FREEDOM trial – a pivotal trial published in 2009 that demonstrated a favorable risk/benefit profile for denosumab (N. Engl. J. Med. 2009;361:756-65).

The agent subsequently received Food and Drug Administration approval for the treatment of postmenopausal women with osteoporosis and an increased fracture risk.

The annual incidences of new vertebral and nonvertebral fractures were lower in the crossover group in the extension trial than in the FREEDOM placebo group.

During the open-label active treatment extension trial, which was designed to investigate the efficacy and safety of the drug for up to 10 years, participants received 60 mg of denosumab as a subcutaneous injection every 6 months along with daily supplemental calcium and vitamin D. In the first 3 years of the extension trial, those in the long-term treatment group experienced additional, statistically significant increases in bone mineral density (cumulative 6-year gains of 15.2% at the lumbar spine and 7.5% at the total hip), and those in the crossover group experienced significant mean gains in bone mineral density that were similar to those seen initially in the FREEDOM trial active treatment group (9.4% at the lumbar spine and 4.8% at the total hip), Dr. Jacques P. Brown reported during a late-breaking abstract session at the annual meeting of the American College of Rheumatology.

The gains seen in the active treatment group in the FREEDOM trial at 3 years were 10.1% at the lumbar spine and 5.7% at the total hip, said Dr. Brown of Laval University, Quebec City.

Measures of serum carboxy-terminal telopeptide (CTX), which is a marker of bone resorption, demonstrated "a profound reduction in bone resorption" appearing rapidly and similarly after the first treatment in the cross-over group, and after the seventh treatment in the long-term treatment group – with the "characteristic attenuation observed at the end of the dosing period," Dr. Brown said.

The annual incidences of new vertebral and nonvertebral fractures were lower in the crossover group in the extension trial than in the FREEDOM placebo group. Fracture incidence also remained low in the long-term group in the extension trial, he said, noting that adverse events and serious adverse events also did not increase over time in the extension trial, and there were no "significant imbalances between the groups."

Osteonecrosis of the jaw occurred in two patients in both the long-term and crossover treatment groups; in the crossover group, both cases resolved completely within the follow-up period, and one of those patients had continued on treatment. The cases in the long-term treatment group remained unresolved at the time of Dr. Brown’s report.

These interim findings from the FREEDOM extension trial demonstrate that denosumab treatment for up to 6 years lead to continued improvement in women on long-term treatment, and that treatment for up to 3 years in the crossover group largely reproduced the observations in the original FREEDOM denosumab group, Dr. Brown concluded.

Dr. Brown disclosed having various relationships with Abbott, Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Servier, and Warner Chilcott. Other authors on the study also disclosed various relationships with these and/or other pharmaceutical companies.

CHICAGO – Denosumab remained well-tolerated, safe, and effective for maintaining reduced bone turnover and for increasing bone mineral density after 6 years of continuous use in 2,343 postmenopausal women with increased fracture risk due to osteoporosis.

These findings come from the first 3 years of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis) extension trial.

The fully human monoclonal antibody also led to significant gains in bone mineral density in a "crossover" group of 2,207 women who received placebo during the original FREEDOM trial – a pivotal trial published in 2009 that demonstrated a favorable risk/benefit profile for denosumab (N. Engl. J. Med. 2009;361:756-65).

The agent subsequently received Food and Drug Administration approval for the treatment of postmenopausal women with osteoporosis and an increased fracture risk.

The annual incidences of new vertebral and nonvertebral fractures were lower in the crossover group in the extension trial than in the FREEDOM placebo group.

During the open-label active treatment extension trial, which was designed to investigate the efficacy and safety of the drug for up to 10 years, participants received 60 mg of denosumab as a subcutaneous injection every 6 months along with daily supplemental calcium and vitamin D. In the first 3 years of the extension trial, those in the long-term treatment group experienced additional, statistically significant increases in bone mineral density (cumulative 6-year gains of 15.2% at the lumbar spine and 7.5% at the total hip), and those in the crossover group experienced significant mean gains in bone mineral density that were similar to those seen initially in the FREEDOM trial active treatment group (9.4% at the lumbar spine and 4.8% at the total hip), Dr. Jacques P. Brown reported during a late-breaking abstract session at the annual meeting of the American College of Rheumatology.

The gains seen in the active treatment group in the FREEDOM trial at 3 years were 10.1% at the lumbar spine and 5.7% at the total hip, said Dr. Brown of Laval University, Quebec City.

Measures of serum carboxy-terminal telopeptide (CTX), which is a marker of bone resorption, demonstrated "a profound reduction in bone resorption" appearing rapidly and similarly after the first treatment in the cross-over group, and after the seventh treatment in the long-term treatment group – with the "characteristic attenuation observed at the end of the dosing period," Dr. Brown said.

The annual incidences of new vertebral and nonvertebral fractures were lower in the crossover group in the extension trial than in the FREEDOM placebo group. Fracture incidence also remained low in the long-term group in the extension trial, he said, noting that adverse events and serious adverse events also did not increase over time in the extension trial, and there were no "significant imbalances between the groups."

Osteonecrosis of the jaw occurred in two patients in both the long-term and crossover treatment groups; in the crossover group, both cases resolved completely within the follow-up period, and one of those patients had continued on treatment. The cases in the long-term treatment group remained unresolved at the time of Dr. Brown’s report.

These interim findings from the FREEDOM extension trial demonstrate that denosumab treatment for up to 6 years lead to continued improvement in women on long-term treatment, and that treatment for up to 3 years in the crossover group largely reproduced the observations in the original FREEDOM denosumab group, Dr. Brown concluded.

Dr. Brown disclosed having various relationships with Abbott, Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Servier, and Warner Chilcott. Other authors on the study also disclosed various relationships with these and/or other pharmaceutical companies.

CHICAGO – Patients who undergo total knee replacement surgery recover just as well with postoperative, group-based, outpatient physiotherapy or a monitored, home-based physiotherapy program as with a one-on-one, outpatient center–based program, according to findings from a randomized study involving 249 patients.

With the exception of patient satisfaction with physiotherapy – which was significantly greater for the 85 patients who were randomized to one-on-one therapy and the 84 who were randomized to group-based therapy than it was for the 80 patients who received home-based therapy (mean satisfaction rates, 90%, 84%, and 73%, respectively) – no significant differences were seen in any other outcome measures during the first postsurgical year, Victoria W.M. Ko of the University of New South Wales, Sydney, and her colleagues reported in a poster at the annual meeting of the American College of Rheumatology.

For example, WOMAC (Western Ontario and McMaster Universities) Osteoarthritis Index function scores at postoperative week 10 (the primary outcome measure) were similar at a mean of 44.0, 39.32, and 35.0 in the one-on-one patients, the group-based therapy patients, and the home-based therapy patients, respectively. There also were no differences among groups in recovery of mobility as measured by a 6-minute walk distance and a timed stair test, or in HRQOL (Health-Related Quality of Life) score, knee range of motion, or patient-related overall recovery at 52 weeks, the investigators found.

Furthermore, the home-based program patients were no more likely than those in the other groups to be readmitted to the hospital or to experience any other complications.

Patient in the single-blind study were consecutive adults (mean age, 67 years) who were awaiting total knee replacement, were enrolled 2 weeks prior to surgery, and were randomized 2 weeks after surgery. During the 6-week therapy period, those who were randomized to receive one-on-one therapy or group-based therapy received 12 physiotherapy sessions, and those in the home-based program were prescribed home exercises supplemented with two sessions of one-on-one therapy and a telephone follow-up. All patients were assessed preoperatively and at postoperative weeks 2, 10, 26, and 52.

The findings are important because of the increasing volume of total knee replacement surgeries performed annually, and because home-based therapy provides a safe and more resource-efficient alternative to center-based physiotherapy, the investigators concluded. They added that this approach "will also circumvent access issues frequently associated with center-based care."

The authors reported that they had no disclosures relevant to this study.

CHICAGO – Patients who undergo total knee replacement surgery recover just as well with postoperative, group-based, outpatient physiotherapy or a monitored, home-based physiotherapy program as with a one-on-one, outpatient center–based program, according to findings from a randomized study involving 249 patients.

With the exception of patient satisfaction with physiotherapy – which was significantly greater for the 85 patients who were randomized to one-on-one therapy and the 84 who were randomized to group-based therapy than it was for the 80 patients who received home-based therapy (mean satisfaction rates, 90%, 84%, and 73%, respectively) – no significant differences were seen in any other outcome measures during the first postsurgical year, Victoria W.M. Ko of the University of New South Wales, Sydney, and her colleagues reported in a poster at the annual meeting of the American College of Rheumatology.

For example, WOMAC (Western Ontario and McMaster Universities) Osteoarthritis Index function scores at postoperative week 10 (the primary outcome measure) were similar at a mean of 44.0, 39.32, and 35.0 in the one-on-one patients, the group-based therapy patients, and the home-based therapy patients, respectively. There also were no differences among groups in recovery of mobility as measured by a 6-minute walk distance and a timed stair test, or in HRQOL (Health-Related Quality of Life) score, knee range of motion, or patient-related overall recovery at 52 weeks, the investigators found.

Furthermore, the home-based program patients were no more likely than those in the other groups to be readmitted to the hospital or to experience any other complications.

Patient in the single-blind study were consecutive adults (mean age, 67 years) who were awaiting total knee replacement, were enrolled 2 weeks prior to surgery, and were randomized 2 weeks after surgery. During the 6-week therapy period, those who were randomized to receive one-on-one therapy or group-based therapy received 12 physiotherapy sessions, and those in the home-based program were prescribed home exercises supplemented with two sessions of one-on-one therapy and a telephone follow-up. All patients were assessed preoperatively and at postoperative weeks 2, 10, 26, and 52.

The findings are important because of the increasing volume of total knee replacement surgeries performed annually, and because home-based therapy provides a safe and more resource-efficient alternative to center-based physiotherapy, the investigators concluded. They added that this approach "will also circumvent access issues frequently associated with center-based care."

The authors reported that they had no disclosures relevant to this study.

CHICAGO – Patients who undergo total knee replacement surgery recover just as well with postoperative, group-based, outpatient physiotherapy or a monitored, home-based physiotherapy program as with a one-on-one, outpatient center–based program, according to findings from a randomized study involving 249 patients.

With the exception of patient satisfaction with physiotherapy – which was significantly greater for the 85 patients who were randomized to one-on-one therapy and the 84 who were randomized to group-based therapy than it was for the 80 patients who received home-based therapy (mean satisfaction rates, 90%, 84%, and 73%, respectively) – no significant differences were seen in any other outcome measures during the first postsurgical year, Victoria W.M. Ko of the University of New South Wales, Sydney, and her colleagues reported in a poster at the annual meeting of the American College of Rheumatology.

For example, WOMAC (Western Ontario and McMaster Universities) Osteoarthritis Index function scores at postoperative week 10 (the primary outcome measure) were similar at a mean of 44.0, 39.32, and 35.0 in the one-on-one patients, the group-based therapy patients, and the home-based therapy patients, respectively. There also were no differences among groups in recovery of mobility as measured by a 6-minute walk distance and a timed stair test, or in HRQOL (Health-Related Quality of Life) score, knee range of motion, or patient-related overall recovery at 52 weeks, the investigators found.

Furthermore, the home-based program patients were no more likely than those in the other groups to be readmitted to the hospital or to experience any other complications.

Patient in the single-blind study were consecutive adults (mean age, 67 years) who were awaiting total knee replacement, were enrolled 2 weeks prior to surgery, and were randomized 2 weeks after surgery. During the 6-week therapy period, those who were randomized to receive one-on-one therapy or group-based therapy received 12 physiotherapy sessions, and those in the home-based program were prescribed home exercises supplemented with two sessions of one-on-one therapy and a telephone follow-up. All patients were assessed preoperatively and at postoperative weeks 2, 10, 26, and 52.

The findings are important because of the increasing volume of total knee replacement surgeries performed annually, and because home-based therapy provides a safe and more resource-efficient alternative to center-based physiotherapy, the investigators concluded. They added that this approach "will also circumvent access issues frequently associated with center-based care."

The authors reported that they had no disclosures relevant to this study.

CHICAGO – Mavrilimumab has shown promise for the treatment of rheumatoid arthritis in a randomized, placebo-controlled, phase II study.

The agent is a novel human monoclonal antibody that targets granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) alpha, which has been implicated in the rheumatoid arthritis (RA) disease process by findings from prior preclinical and animal studies.

During the 12-week, dose-ranging study, 55.7% of 149 patients who were randomized to receive 10, 30, 50, or 100 mg of active treatment achieved the primary end point of at least a 1.2-point reduction in the Disease Activity Score 28 as measured using C-reactive protein (DAS28-CRP), compared with only 34.7% of 67 patients randomized to receive placebo. The difference was statistically significant, Dr. Gerd R. Burmester reported at the annual meeting of the American College of Rheumatology.

Response generally occurred within 2 weeks of treatment initiation, and the most significant improvement was seen in patients who were randomized to receive 100 mg of mavrilimumab, with 66.7%, of patients in the 100-mg group achieving the primary end point, compared with 41.0%, 61.0%, and 53.8% of those in the 10-, 30-, and 50-mg groups, respectively, said Dr. Burmester, professor of medicine in the department of rheumatology and clinical immunology at Charité Universitätsmedizin Berlin.

Patients receiving active treatment also were more likely than those receiving placebo to achieve DAS28-CRP remission, with significantly higher remission rates seen both overall (18.4%) and in the 100-mg group (23.1%), compared with placebo (6.7%). ACR 20, 50, and 70 responses (American College of Rheumatology assessment scales based on 20%, 50%, and 70% improvement in specified parameters) were also better in the mavrilimumab patients, compared with the placebo patients, with significantly better improvement seen between the 100-mg group and the placebo group for all three ACR response categories, as well as overall and in the 30-mg group, compared with placebo, for the ACR 50 response category.

Mavrilimumab patients also were more likely to achieve a 0.25-point improvement in HAQ-DI (Health Assessment Questionnaire–Disability Index) scores, compared with placebo patients, with significant differences in the response rates occurring both overall (63.3%) and in the 100-mg group (74.4%), compared with placebo (48.0%), Dr. Burmester said.

Treatment in this study was well tolerated.

"Basically, there were very, very few safety signals at all," he said, noting that serious adverse events were reported in 1.3% and 1.9% of mavrilimumab and placebo patients, respectively, and that none of those events was treatment related.

Other adverse events included a decrease in carbon monoxide diffusing capacity and nasopharyngitis, which each occurred more often in the mavrilimumab patients vs. the placebo patients (11.9% vs. 5.1%, and 6.3% vs. 2.5%, respectively), and upper respiratory infections, which occurred more often in the placebo patients (3.8% vs. 5.1%). These events were generally mild or moderate in intensity.

No significant hypersensitivity reactions, anaphylaxis, opportunistic infections, or pulmonary parameters were reported, Dr. Burmester said.

Study participants were adults from Eastern Europe who had active adult-onset RA of at least 3 months’ duration, and who were positive for anti–cyclic citrullinated protein antibody and/or rheumatoid factor. They had a DAS28-CRP of at least 3.2 at baseline.

"We believe the results from this study suggest that suppressing macrophage activity and targeting the GM-CSF receptor may be a novel approach to the treatment of rheumatoid arthritis," Dr. Burmester said, concluding that the rapid and significant clinical effects seen in the study, as well as the acceptable short-term safety profile, support further clinical development of mavrilimumab.

Dr. Burmester disclosed that he has received consulting fees or other remuneration from Medimmune Ltd., the maker of mavrilimumab. Several other authors on this study also disclosed financial relationships with Medimmune and/or AstraZeneca.

CHICAGO – Mavrilimumab has shown promise for the treatment of rheumatoid arthritis in a randomized, placebo-controlled, phase II study.

The agent is a novel human monoclonal antibody that targets granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) alpha, which has been implicated in the rheumatoid arthritis (RA) disease process by findings from prior preclinical and animal studies.

During the 12-week, dose-ranging study, 55.7% of 149 patients who were randomized to receive 10, 30, 50, or 100 mg of active treatment achieved the primary end point of at least a 1.2-point reduction in the Disease Activity Score 28 as measured using C-reactive protein (DAS28-CRP), compared with only 34.7% of 67 patients randomized to receive placebo. The difference was statistically significant, Dr. Gerd R. Burmester reported at the annual meeting of the American College of Rheumatology.

Response generally occurred within 2 weeks of treatment initiation, and the most significant improvement was seen in patients who were randomized to receive 100 mg of mavrilimumab, with 66.7%, of patients in the 100-mg group achieving the primary end point, compared with 41.0%, 61.0%, and 53.8% of those in the 10-, 30-, and 50-mg groups, respectively, said Dr. Burmester, professor of medicine in the department of rheumatology and clinical immunology at Charité Universitätsmedizin Berlin.

Patients receiving active treatment also were more likely than those receiving placebo to achieve DAS28-CRP remission, with significantly higher remission rates seen both overall (18.4%) and in the 100-mg group (23.1%), compared with placebo (6.7%). ACR 20, 50, and 70 responses (American College of Rheumatology assessment scales based on 20%, 50%, and 70% improvement in specified parameters) were also better in the mavrilimumab patients, compared with the placebo patients, with significantly better improvement seen between the 100-mg group and the placebo group for all three ACR response categories, as well as overall and in the 30-mg group, compared with placebo, for the ACR 50 response category.

Mavrilimumab patients also were more likely to achieve a 0.25-point improvement in HAQ-DI (Health Assessment Questionnaire–Disability Index) scores, compared with placebo patients, with significant differences in the response rates occurring both overall (63.3%) and in the 100-mg group (74.4%), compared with placebo (48.0%), Dr. Burmester said.

Treatment in this study was well tolerated.

"Basically, there were very, very few safety signals at all," he said, noting that serious adverse events were reported in 1.3% and 1.9% of mavrilimumab and placebo patients, respectively, and that none of those events was treatment related.

Other adverse events included a decrease in carbon monoxide diffusing capacity and nasopharyngitis, which each occurred more often in the mavrilimumab patients vs. the placebo patients (11.9% vs. 5.1%, and 6.3% vs. 2.5%, respectively), and upper respiratory infections, which occurred more often in the placebo patients (3.8% vs. 5.1%). These events were generally mild or moderate in intensity.

No significant hypersensitivity reactions, anaphylaxis, opportunistic infections, or pulmonary parameters were reported, Dr. Burmester said.

Study participants were adults from Eastern Europe who had active adult-onset RA of at least 3 months’ duration, and who were positive for anti–cyclic citrullinated protein antibody and/or rheumatoid factor. They had a DAS28-CRP of at least 3.2 at baseline.

"We believe the results from this study suggest that suppressing macrophage activity and targeting the GM-CSF receptor may be a novel approach to the treatment of rheumatoid arthritis," Dr. Burmester said, concluding that the rapid and significant clinical effects seen in the study, as well as the acceptable short-term safety profile, support further clinical development of mavrilimumab.

Dr. Burmester disclosed that he has received consulting fees or other remuneration from Medimmune Ltd., the maker of mavrilimumab. Several other authors on this study also disclosed financial relationships with Medimmune and/or AstraZeneca.

CHICAGO – Mavrilimumab has shown promise for the treatment of rheumatoid arthritis in a randomized, placebo-controlled, phase II study.

The agent is a novel human monoclonal antibody that targets granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) alpha, which has been implicated in the rheumatoid arthritis (RA) disease process by findings from prior preclinical and animal studies.

During the 12-week, dose-ranging study, 55.7% of 149 patients who were randomized to receive 10, 30, 50, or 100 mg of active treatment achieved the primary end point of at least a 1.2-point reduction in the Disease Activity Score 28 as measured using C-reactive protein (DAS28-CRP), compared with only 34.7% of 67 patients randomized to receive placebo. The difference was statistically significant, Dr. Gerd R. Burmester reported at the annual meeting of the American College of Rheumatology.

Response generally occurred within 2 weeks of treatment initiation, and the most significant improvement was seen in patients who were randomized to receive 100 mg of mavrilimumab, with 66.7%, of patients in the 100-mg group achieving the primary end point, compared with 41.0%, 61.0%, and 53.8% of those in the 10-, 30-, and 50-mg groups, respectively, said Dr. Burmester, professor of medicine in the department of rheumatology and clinical immunology at Charité Universitätsmedizin Berlin.

Patients receiving active treatment also were more likely than those receiving placebo to achieve DAS28-CRP remission, with significantly higher remission rates seen both overall (18.4%) and in the 100-mg group (23.1%), compared with placebo (6.7%). ACR 20, 50, and 70 responses (American College of Rheumatology assessment scales based on 20%, 50%, and 70% improvement in specified parameters) were also better in the mavrilimumab patients, compared with the placebo patients, with significantly better improvement seen between the 100-mg group and the placebo group for all three ACR response categories, as well as overall and in the 30-mg group, compared with placebo, for the ACR 50 response category.

Mavrilimumab patients also were more likely to achieve a 0.25-point improvement in HAQ-DI (Health Assessment Questionnaire–Disability Index) scores, compared with placebo patients, with significant differences in the response rates occurring both overall (63.3%) and in the 100-mg group (74.4%), compared with placebo (48.0%), Dr. Burmester said.

Treatment in this study was well tolerated.

"Basically, there were very, very few safety signals at all," he said, noting that serious adverse events were reported in 1.3% and 1.9% of mavrilimumab and placebo patients, respectively, and that none of those events was treatment related.

Other adverse events included a decrease in carbon monoxide diffusing capacity and nasopharyngitis, which each occurred more often in the mavrilimumab patients vs. the placebo patients (11.9% vs. 5.1%, and 6.3% vs. 2.5%, respectively), and upper respiratory infections, which occurred more often in the placebo patients (3.8% vs. 5.1%). These events were generally mild or moderate in intensity.

No significant hypersensitivity reactions, anaphylaxis, opportunistic infections, or pulmonary parameters were reported, Dr. Burmester said.

Study participants were adults from Eastern Europe who had active adult-onset RA of at least 3 months’ duration, and who were positive for anti–cyclic citrullinated protein antibody and/or rheumatoid factor. They had a DAS28-CRP of at least 3.2 at baseline.

"We believe the results from this study suggest that suppressing macrophage activity and targeting the GM-CSF receptor may be a novel approach to the treatment of rheumatoid arthritis," Dr. Burmester said, concluding that the rapid and significant clinical effects seen in the study, as well as the acceptable short-term safety profile, support further clinical development of mavrilimumab.

Dr. Burmester disclosed that he has received consulting fees or other remuneration from Medimmune Ltd., the maker of mavrilimumab. Several other authors on this study also disclosed financial relationships with Medimmune and/or AstraZeneca.

CHICAGO – The novel oral chemokine receptor 1 antagonist CCX354-C was safe and well tolerated and had encouraging clinical and biologic activity against rheumatoid arthritis in a randomized, controlled, phase II study involving 160 patients.

The primary end point of the study was safety and tolerability, but the findings of clinical efficacy in rheumatoid arthritis (RA) mark a first for a chemokine receptor 1 (CCR1) blocker. Such agents have, however, been previously shown to have activity in in vitro models and in a synovial biopsy study in humans. It is well documented that high levels of CCR1-expressing macrophages and CCR1 chemokines can be found in inflamed synovial fluids and tissues in RA, Dr. Paul P. Tak reported at the annual meeting of the American College of Rheumatology.

In the current study, CCX354-C was given at doses of 100 or 200 mg twice daily. Compared with placebo, the 200-mg dose was associated with the greatest efficacy. ACR20 response rates among day 1 eligible subjects in an intention-to-treat analysis, for example, were 56%, 44%, and 30%, in the 200-mg, 100-mg, and placebo groups, respectively, said Dr. Tak of the division of clinical immunology and rheumatology at the Academic Medical Center of the University of Amsterdam.

Significant differences were also seen between patients given CCX354-C or placebo who were biologics naive; ACR20 response rates in these patients were 62%, 42%, and 27% in the 200-mg, 100-mg, and placebo groups, respectively.

C-reactive protein (CRP) levels decreased with treatment, with significantly greater decreases seen in the 200-mg group, compared with placebo. Levels of C-terminal telopeptide (CTx), procollagen type I N-terminal propepetide (PINP), and osteocalcin decreased significantly more in the treatment groups than in the placebo group at several points during the study, Dr. Tak said.

Study participants had moderate to severe RA and were on stable doses of methotrexate for at least 8 weeks at study entry. All had swollen and tender joint counts of 8 or greater, as well as CRP levels greater than 5 mg/L. Most (84%) were women, and the median age of all participants was 55 years. Median disease duration was 5 years, median DAS28 as determined by CRP level (DAS28-CRP) score was 5.8, median CRP was 11 mg/L, and median erythrocyte sedimentation rate was 34 mm/hr.

Most patients (88%) were biologics naive, and a little more than half (55%) were current corticosteroid users.

No serious adverse events were reported in either the 200-mg group or the placebo group; four serious adverse events occurred in the 100-mg treatment group, but these were not considered to be related to the study drug, Dr. Tak noted.

"To take this altogether, CCX354-C shows promise as an orally delivered CCR-1 antagonist for the treatment of rheumatoid arthritis," he said.

Dr. Tak disclosed that he has financial relationships with Abbott Laboratories, Arthrogen B.V., AstraZeneca, Bristol-Meyers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MerckSerono, NovoNordisk, Pfizer Inc., and Roche Pharmaceuticals. Several other authors of the study are employed by, or have another type of relationship with ChemoCentryx, which is the maker of CCX354-C.

CHICAGO – The novel oral chemokine receptor 1 antagonist CCX354-C was safe and well tolerated and had encouraging clinical and biologic activity against rheumatoid arthritis in a randomized, controlled, phase II study involving 160 patients.

The primary end point of the study was safety and tolerability, but the findings of clinical efficacy in rheumatoid arthritis (RA) mark a first for a chemokine receptor 1 (CCR1) blocker. Such agents have, however, been previously shown to have activity in in vitro models and in a synovial biopsy study in humans. It is well documented that high levels of CCR1-expressing macrophages and CCR1 chemokines can be found in inflamed synovial fluids and tissues in RA, Dr. Paul P. Tak reported at the annual meeting of the American College of Rheumatology.

In the current study, CCX354-C was given at doses of 100 or 200 mg twice daily. Compared with placebo, the 200-mg dose was associated with the greatest efficacy. ACR20 response rates among day 1 eligible subjects in an intention-to-treat analysis, for example, were 56%, 44%, and 30%, in the 200-mg, 100-mg, and placebo groups, respectively, said Dr. Tak of the division of clinical immunology and rheumatology at the Academic Medical Center of the University of Amsterdam.

Significant differences were also seen between patients given CCX354-C or placebo who were biologics naive; ACR20 response rates in these patients were 62%, 42%, and 27% in the 200-mg, 100-mg, and placebo groups, respectively.

C-reactive protein (CRP) levels decreased with treatment, with significantly greater decreases seen in the 200-mg group, compared with placebo. Levels of C-terminal telopeptide (CTx), procollagen type I N-terminal propepetide (PINP), and osteocalcin decreased significantly more in the treatment groups than in the placebo group at several points during the study, Dr. Tak said.

Study participants had moderate to severe RA and were on stable doses of methotrexate for at least 8 weeks at study entry. All had swollen and tender joint counts of 8 or greater, as well as CRP levels greater than 5 mg/L. Most (84%) were women, and the median age of all participants was 55 years. Median disease duration was 5 years, median DAS28 as determined by CRP level (DAS28-CRP) score was 5.8, median CRP was 11 mg/L, and median erythrocyte sedimentation rate was 34 mm/hr.

Most patients (88%) were biologics naive, and a little more than half (55%) were current corticosteroid users.

No serious adverse events were reported in either the 200-mg group or the placebo group; four serious adverse events occurred in the 100-mg treatment group, but these were not considered to be related to the study drug, Dr. Tak noted.

"To take this altogether, CCX354-C shows promise as an orally delivered CCR-1 antagonist for the treatment of rheumatoid arthritis," he said.

Dr. Tak disclosed that he has financial relationships with Abbott Laboratories, Arthrogen B.V., AstraZeneca, Bristol-Meyers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MerckSerono, NovoNordisk, Pfizer Inc., and Roche Pharmaceuticals. Several other authors of the study are employed by, or have another type of relationship with ChemoCentryx, which is the maker of CCX354-C.

CHICAGO – The novel oral chemokine receptor 1 antagonist CCX354-C was safe and well tolerated and had encouraging clinical and biologic activity against rheumatoid arthritis in a randomized, controlled, phase II study involving 160 patients.

The primary end point of the study was safety and tolerability, but the findings of clinical efficacy in rheumatoid arthritis (RA) mark a first for a chemokine receptor 1 (CCR1) blocker. Such agents have, however, been previously shown to have activity in in vitro models and in a synovial biopsy study in humans. It is well documented that high levels of CCR1-expressing macrophages and CCR1 chemokines can be found in inflamed synovial fluids and tissues in RA, Dr. Paul P. Tak reported at the annual meeting of the American College of Rheumatology.

In the current study, CCX354-C was given at doses of 100 or 200 mg twice daily. Compared with placebo, the 200-mg dose was associated with the greatest efficacy. ACR20 response rates among day 1 eligible subjects in an intention-to-treat analysis, for example, were 56%, 44%, and 30%, in the 200-mg, 100-mg, and placebo groups, respectively, said Dr. Tak of the division of clinical immunology and rheumatology at the Academic Medical Center of the University of Amsterdam.

Significant differences were also seen between patients given CCX354-C or placebo who were biologics naive; ACR20 response rates in these patients were 62%, 42%, and 27% in the 200-mg, 100-mg, and placebo groups, respectively.

C-reactive protein (CRP) levels decreased with treatment, with significantly greater decreases seen in the 200-mg group, compared with placebo. Levels of C-terminal telopeptide (CTx), procollagen type I N-terminal propepetide (PINP), and osteocalcin decreased significantly more in the treatment groups than in the placebo group at several points during the study, Dr. Tak said.

Study participants had moderate to severe RA and were on stable doses of methotrexate for at least 8 weeks at study entry. All had swollen and tender joint counts of 8 or greater, as well as CRP levels greater than 5 mg/L. Most (84%) were women, and the median age of all participants was 55 years. Median disease duration was 5 years, median DAS28 as determined by CRP level (DAS28-CRP) score was 5.8, median CRP was 11 mg/L, and median erythrocyte sedimentation rate was 34 mm/hr.

Most patients (88%) were biologics naive, and a little more than half (55%) were current corticosteroid users.

No serious adverse events were reported in either the 200-mg group or the placebo group; four serious adverse events occurred in the 100-mg treatment group, but these were not considered to be related to the study drug, Dr. Tak noted.

"To take this altogether, CCX354-C shows promise as an orally delivered CCR-1 antagonist for the treatment of rheumatoid arthritis," he said.

Dr. Tak disclosed that he has financial relationships with Abbott Laboratories, Arthrogen B.V., AstraZeneca, Bristol-Meyers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MerckSerono, NovoNordisk, Pfizer Inc., and Roche Pharmaceuticals. Several other authors of the study are employed by, or have another type of relationship with ChemoCentryx, which is the maker of CCX354-C.