RA: Adalimumab, MTX Induction Yields Sustained Response

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After 24 weeks, adalimumab was withdrawn in the patients on combination therapy, and both groups received only methotrexate for an additional 24 weeks.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.