Early aggressive therapy in JIA brings prolonged disease inactivation

SAN DIEGO – Starting aggressive multidrug therapy within the first several months after children were diagnosed with severe polyarticular juvenile idiopathic arthritis resulted in a "phenomenal" rate of clinical inactive disease, which occurred faster and was sustained longer than with high-dose methotrexate monotherapy in a randomized, double-blind, multicenter clinical trial.

"This is a groundbreaking study. This is the first-ever study in children that has used clinical inactive disease as the primary endpoint. And it showed that clinical inactive disease – or remission, if you’d like – is achievable if you treat early and aggressively," declared Dr. Carol A. Wallace, professor of pediatrics at the University of Washington, Seattle, and rheumatology division chief at Seattle Children’s Hospital.

At the annual meeting of the American College of Rheumatology, she presented a new secondary analysis from the previously reported landmark Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis (TREAT-JIA), in which 85 patients diagnosed a median of 4.2 months prior to enrollment were randomized double-blind to one of two treatment arms: combination therapy with subcutaneous methotrexate at 0.5 mg/kg per week, etanercept at 0.8 mg/kg per week, plus prednisolone at 0.5 mg/kg per day tapered to zero by 17 weeks; or subcutaneous methotrexate dosed identically plus double placebos (Arthritis Rheum. 2012;64:2012-21).

The group on multidrug therapy spent a median of 42% of days during the 12-month study in a state of clinical inactive disease, compared with 24% for patients who started on methotrexate alone. And those figures don’t convey the full impact of combination therapy. Seventeen of the 28 patients in the methotrexate monotherapy group who achieved clinical inactive disease did so only after undergoing a protocol-mandated switch to open-label combination therapy because they failed to receive an ACR 70 response within the first 4 months, yet in the intent-to-treat analysis those 17 patients were counted in the methotrexate-alone group.

The term "clinical inactive disease" is defined stringently in pediatric rheumatology, Dr. Wallace explained. It requires that a patient must have zero joints with active arthritis, no elevation in ESR, no uveitis, a Physician Global Assessment score of 0 on a 0-10 scale, and no fever, rash, hepatosplenomegaly, or lymphadenopathy.

The fact that 68% of study patients achieved clinical inactive disease at some point is particularly impressive in light of their high burden of disease, Dr. Wallace observed. Their baseline Physician Global Assessment score was 7, and nearly 40% of subjects were rheumatoid factor positive.

A major goal in the secondary analysis was to identify predictors of a favorable treatment response. The investigators found two. One was time to treatment. It was a linear relationship: The earlier the treatment began, the more time patients spent in a state of clinical inactive disease. Those who started treatment having a disease duration of 3 months or less had clinical inactive disease at a median of 40% of clinic visits, regardless of treatment arm, while patients who began therapy with a disease duration of more than 3 months had clinical inactive disease at only 11% of visits.

The other predictor of a favorable response was achieving an ACR 70 response at 4 months, regardless of the treatment regimen employed. Among 49 patients who did so, 86% attained clinical inactive disease during the 12-month study, compared with a 44% rate among those who did not achieve the early ACR 70. Nine patients in the multidrug therapy arm and three on methotrexate monotherapy achieved a complete remission, defined as 6 months of continuous clinical inactive disease; all 12 of these patients had an ACR 70 response at 4 months.

Side effects in the two treatment groups were similarly uncommon.

The investigators are now attempting to learn whether the immune system of successfully treated children with juvenile idiopathic arthritis eventually returns to normal, making it safe to discontinue medications. The final word isn’t in yet, but Dr. Wallace is doubtful.

"At least 50% of children do flare when their medications are stopped, and they don’t always achieve the same level of disease response the second time around," said the pediatric rheumatologist.

The TREAT-JIA trial was funded by the National Institute of Allergy and Infectious Diseases and the Howe Endowment for Juvenile Idiopathic Arthritis Research. Dr. Wallace reported having no financial conflicts.

[email protected]

SAN DIEGO – Starting aggressive multidrug therapy within the first several months after children were diagnosed with severe polyarticular juvenile idiopathic arthritis resulted in a "phenomenal" rate of clinical inactive disease, which occurred faster and was sustained longer than with high-dose methotrexate monotherapy in a randomized, double-blind, multicenter clinical trial.

"This is a groundbreaking study. This is the first-ever study in children that has used clinical inactive disease as the primary endpoint. And it showed that clinical inactive disease – or remission, if you’d like – is achievable if you treat early and aggressively," declared Dr. Carol A. Wallace, professor of pediatrics at the University of Washington, Seattle, and rheumatology division chief at Seattle Children’s Hospital.

At the annual meeting of the American College of Rheumatology, she presented a new secondary analysis from the previously reported landmark Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis (TREAT-JIA), in which 85 patients diagnosed a median of 4.2 months prior to enrollment were randomized double-blind to one of two treatment arms: combination therapy with subcutaneous methotrexate at 0.5 mg/kg per week, etanercept at 0.8 mg/kg per week, plus prednisolone at 0.5 mg/kg per day tapered to zero by 17 weeks; or subcutaneous methotrexate dosed identically plus double placebos (Arthritis Rheum. 2012;64:2012-21).

The group on multidrug therapy spent a median of 42% of days during the 12-month study in a state of clinical inactive disease, compared with 24% for patients who started on methotrexate alone. And those figures don’t convey the full impact of combination therapy. Seventeen of the 28 patients in the methotrexate monotherapy group who achieved clinical inactive disease did so only after undergoing a protocol-mandated switch to open-label combination therapy because they failed to receive an ACR 70 response within the first 4 months, yet in the intent-to-treat analysis those 17 patients were counted in the methotrexate-alone group.

The term "clinical inactive disease" is defined stringently in pediatric rheumatology, Dr. Wallace explained. It requires that a patient must have zero joints with active arthritis, no elevation in ESR, no uveitis, a Physician Global Assessment score of 0 on a 0-10 scale, and no fever, rash, hepatosplenomegaly, or lymphadenopathy.

The fact that 68% of study patients achieved clinical inactive disease at some point is particularly impressive in light of their high burden of disease, Dr. Wallace observed. Their baseline Physician Global Assessment score was 7, and nearly 40% of subjects were rheumatoid factor positive.

A major goal in the secondary analysis was to identify predictors of a favorable treatment response. The investigators found two. One was time to treatment. It was a linear relationship: The earlier the treatment began, the more time patients spent in a state of clinical inactive disease. Those who started treatment having a disease duration of 3 months or less had clinical inactive disease at a median of 40% of clinic visits, regardless of treatment arm, while patients who began therapy with a disease duration of more than 3 months had clinical inactive disease at only 11% of visits.

The other predictor of a favorable response was achieving an ACR 70 response at 4 months, regardless of the treatment regimen employed. Among 49 patients who did so, 86% attained clinical inactive disease during the 12-month study, compared with a 44% rate among those who did not achieve the early ACR 70. Nine patients in the multidrug therapy arm and three on methotrexate monotherapy achieved a complete remission, defined as 6 months of continuous clinical inactive disease; all 12 of these patients had an ACR 70 response at 4 months.

Side effects in the two treatment groups were similarly uncommon.

The investigators are now attempting to learn whether the immune system of successfully treated children with juvenile idiopathic arthritis eventually returns to normal, making it safe to discontinue medications. The final word isn’t in yet, but Dr. Wallace is doubtful.

"At least 50% of children do flare when their medications are stopped, and they don’t always achieve the same level of disease response the second time around," said the pediatric rheumatologist.

The TREAT-JIA trial was funded by the National Institute of Allergy and Infectious Diseases and the Howe Endowment for Juvenile Idiopathic Arthritis Research. Dr. Wallace reported having no financial conflicts.

[email protected]

SAN DIEGO – Starting aggressive multidrug therapy within the first several months after children were diagnosed with severe polyarticular juvenile idiopathic arthritis resulted in a "phenomenal" rate of clinical inactive disease, which occurred faster and was sustained longer than with high-dose methotrexate monotherapy in a randomized, double-blind, multicenter clinical trial.

"This is a groundbreaking study. This is the first-ever study in children that has used clinical inactive disease as the primary endpoint. And it showed that clinical inactive disease – or remission, if you’d like – is achievable if you treat early and aggressively," declared Dr. Carol A. Wallace, professor of pediatrics at the University of Washington, Seattle, and rheumatology division chief at Seattle Children’s Hospital.

At the annual meeting of the American College of Rheumatology, she presented a new secondary analysis from the previously reported landmark Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis (TREAT-JIA), in which 85 patients diagnosed a median of 4.2 months prior to enrollment were randomized double-blind to one of two treatment arms: combination therapy with subcutaneous methotrexate at 0.5 mg/kg per week, etanercept at 0.8 mg/kg per week, plus prednisolone at 0.5 mg/kg per day tapered to zero by 17 weeks; or subcutaneous methotrexate dosed identically plus double placebos (Arthritis Rheum. 2012;64:2012-21).

The group on multidrug therapy spent a median of 42% of days during the 12-month study in a state of clinical inactive disease, compared with 24% for patients who started on methotrexate alone. And those figures don’t convey the full impact of combination therapy. Seventeen of the 28 patients in the methotrexate monotherapy group who achieved clinical inactive disease did so only after undergoing a protocol-mandated switch to open-label combination therapy because they failed to receive an ACR 70 response within the first 4 months, yet in the intent-to-treat analysis those 17 patients were counted in the methotrexate-alone group.

The term "clinical inactive disease" is defined stringently in pediatric rheumatology, Dr. Wallace explained. It requires that a patient must have zero joints with active arthritis, no elevation in ESR, no uveitis, a Physician Global Assessment score of 0 on a 0-10 scale, and no fever, rash, hepatosplenomegaly, or lymphadenopathy.

The fact that 68% of study patients achieved clinical inactive disease at some point is particularly impressive in light of their high burden of disease, Dr. Wallace observed. Their baseline Physician Global Assessment score was 7, and nearly 40% of subjects were rheumatoid factor positive.

A major goal in the secondary analysis was to identify predictors of a favorable treatment response. The investigators found two. One was time to treatment. It was a linear relationship: The earlier the treatment began, the more time patients spent in a state of clinical inactive disease. Those who started treatment having a disease duration of 3 months or less had clinical inactive disease at a median of 40% of clinic visits, regardless of treatment arm, while patients who began therapy with a disease duration of more than 3 months had clinical inactive disease at only 11% of visits.

The other predictor of a favorable response was achieving an ACR 70 response at 4 months, regardless of the treatment regimen employed. Among 49 patients who did so, 86% attained clinical inactive disease during the 12-month study, compared with a 44% rate among those who did not achieve the early ACR 70. Nine patients in the multidrug therapy arm and three on methotrexate monotherapy achieved a complete remission, defined as 6 months of continuous clinical inactive disease; all 12 of these patients had an ACR 70 response at 4 months.

Side effects in the two treatment groups were similarly uncommon.

The investigators are now attempting to learn whether the immune system of successfully treated children with juvenile idiopathic arthritis eventually returns to normal, making it safe to discontinue medications. The final word isn’t in yet, but Dr. Wallace is doubtful.

"At least 50% of children do flare when their medications are stopped, and they don’t always achieve the same level of disease response the second time around," said the pediatric rheumatologist.

The TREAT-JIA trial was funded by the National Institute of Allergy and Infectious Diseases and the Howe Endowment for Juvenile Idiopathic Arthritis Research. Dr. Wallace reported having no financial conflicts.

[email protected]