Treating JIA Early: The Future May Be Here

Can early, aggressive treatment stop the often-relentless march of juvenile idiopathic arthritis?

Is there a short window of opportunity, early in the disease, to radically change its course and prevent joint damage?

Is inactive disease not only a worthy – but entirely possible – goal for children with JIA?

Within 6 months, according to Dr. Carol A. Wallace, findings from a small but powerful clinical trial could answer these questions, carrying the potential to completely change the treatment approach used in young patients with JIA.

"I think evidence is growing that early, aggressive therapy can fundamentally change this disease in the first year after diagnosis," she said in an interview. "And if we are looking at an opportunity for change, it behooves us to do everything possible to hit this disease early and hard."

At the annual meeting of the Pediatric Rheumatology European Society, Dr. Wallace, a pediatric rheumatologist and researcher at Seattle Children’s Hospital, spoke about what has, in the past, been considered an unrealistic goal: turning a progressive childhood rheumatologic disease into a manageable disorder, with a minimum of medical therapy and a maximum quality of life.

"People have long underestimated the burden of this disease in children," she said. "They haven’t recognized the value of completely inactive disease, or understood that having no disease activity is a truly achievable goal."

Traditionally, the JIA treatment mantra has been "start low, go slow," adding more powerful medications only as symptoms increase and joint damage becomes apparent. But in the last 10 years or so, researchers have begun to ask another question: What would happen if we hit JIA with more effective treatments, earlier on?

For some, the idea has been a hard sell.

"Yes, our most effective medications are expensive, high powered, and with potential side effects, so many physicians are afraid of using them in children," Dr. Wallace said. "But on the other hand, what would be the real value of inactive disease for these kids? What if they could have a very high quality of life – running around and playing soccer – instead of going to the doctor frequently? Getting off medication sooner could mean less overall drug exposure" than that experienced by children who are treated with less-powerful medications but who, after years of treatment, are still on drugs with active or smoldering disease.

Even administrators who guard the bottom line could be happier because of the expected savings, she said. "This way of treating might actually be more cost effective in the long run. With better quality of life and inactive disease, there could be fewer visits to the doctor, less overall utilization of health care resources, fewer joint replacements, fewer parents missing work for a child’s illness – there are a lot of purely economic ramifications from having complete disease response."

Bit by bit, the evidence supporting this idea has grown, she said at the meeting. In 2008, a retrospective study of 125 patients with at least 5 years of follow-up found that those who achieved an ACR Pedi 70 (American College of Rheumatology Pediatric 70) score by 6 months after initiation of treatment showed sustained, significantly greater improvement over the long run than did nonresponders. At the end of the study, 55% of the responders had inactive disease, compared with 17% of the nonresponders and 29% of those who responded less favorably to treatment (Ann. Rheum. Dis. 2008;67:370-4).

Imaging studies have shown that joint damage in JIA progresses fastest during the first year of the disease. A 2005 study of 13 children with newly diagnosed polyarticular JIA found progressive joint damage in six children after only 14 months. These children started disease-modifying antirheumatic drugs (DMARDs) at an average of 7.5 months after symptoms appeared. The others – who started DMARDs earlier, at an average of 1.6 months after diagnosis – had no progression (Ann. Rheum. Dis. 2005:64:491-3).

Findings from studies involving adults send a similar message: Treatment timing matters. "The evidence tells us that the disease continues to spread to additional joints, and the burden of disease becomes greater with time," Dr. Wallace said. "The adult and pediatric evidence now tells us that if we treat earlier and get it quieted down early, patients do better in the long run."

The data also confirm that treatment type matters. The most recent evidence comes from a 2010 meta-analysis of 15 randomized, controlled trials comprising 4,200 patients with rheumatoid arthritis of less than 3 years’ duration. Treatment regimens in the studies included DMARDs, a combination of tumor necrosis factor (TNF) blockers plus methotrexate, and methotrexate alone. "Both the DMARDs and the combination therapy were superior to methotrexate alone," Dr. Wallace said. Patients taking the anti-TNF and methotrexate had higher ACR responses, fewer withdrawals for inefficacy or toxicity, lower disability scores, and less erosive damage on imaging (Rheumatology 2010;49:91-8).

Again, childhood data show similar findings. A study reported at the 2009 ACR annual meeting randomized 60 DMARD-naive JIA patients with just 6 weeks’ disease duration to methotrexate, methotrexate plus infliximab, or a combo of methotrexate, sulfasalazine, and hydroxychloroquine. At 6 months, an ACR Pedi 75 response occurred in 100% of the double therapy group, 65% of the triple therapy group, and 10% of the methotrexate-only group. By 54 weeks, 68% of the double therapy, 40% of the triple therapy, and 25% of the methotrexate groups had inactive disease.

All of these encouraging data lead to the TREAT (Trial of Early Aggressive Therapy) in JIA trial, the results of which Dr. Carol Wallace is eagerly awaiting. The yearlong study randomized 85 children with polyarticular or extended oligoarticular JIA to one of two aggressive treatment regimens. Because all of the subjects had a disease duration of less than 12 months, TREAT may provide answers about optimal timing as well as optimal therapy.

The study is being conducted by CARRA (Childhood Arthritis and Rheumatology Research Alliance). Founded by researchers, CARRA conducts investigator-initiated clinical trials not only for JIA, but also for other childhood rheumatic diseases (www.carragroup.org). CARRA now comprises 92 pediatric rheumatology centers and more than 300 clinician members all over North America.

TREAT was conducted at 15 CARRA sites. Both weekly treatment arms included subcutaneous methotrexate at 0.5 mg/kg. Group A also received placebo etanercept, folate, NSAIDs as necessary, and a placebo prednisone taper. Group B received, in addition to methotrexate, weekly subcutaneous injections of etanercept at 0.8 mg/kg; folate; NSAIDs as needed; and a 4-month prednisone taper that started at 0.5 mg/kg.

The study’s primary end point is the rate of inactive disease at 6 months. Secondary end points include the rate of ACR Pedi 70 by 4 months; clinical remission on medication by 12 months; safety of the treatment, and MRI of the knee to show potential biologic changes associated with active and inactive disease.

The children’s mean age was 11 years and their mean disease duration was just over 4 months. They had a mean of 22 active joints and a mean erythrocyte sedimentation rate of 37. Their mean Physician Global Assessment score was nearly 7. Most of the children (69%) were positive for antinuclear antibodies; 36% were rheumatoid factor positive.

The last subject visits have just occurred, and so full data analysis has not been completed. Dr. Wallace said that 77 patients finished out the pivotal first 6 months of the trial. At that point, those who achieved a state of inactive disease continued on their assigned treatment arm until the end of the trial, or until they had a flare. Those who still had active disease at 6 months could opt for up to 6 months of open-label etanercept plus methotrexate and a prednisone taper, or up to two intra-articular injections while continuing on their blinded treatment. If they then experienced a flare, they discontinued the trial.

By the end of October, 67 patients (77%) had completed 12 months of the trial. Dr. Wallace and her coinvestigators expect to release the results in the first quarter of 2011.

Despite its relatively small size, she said, TREAT could be practice transforming. "Whatever the result, we plan to deploy this treatment as quickly as we can in clinical practice. That’s actually the beauty of the CARRA network. We can, through our members, make a standard of care based on data. And that’s what this study is all about – finding evidence. We must continue to look for evidence that supports the best way to treat JIA."

Although Amgen supplied the etanercept for TREAT, the study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. Dr. Wallace has no financial disclosures with regard to the study.

Can early, aggressive treatment stop the often-relentless march of juvenile idiopathic arthritis?

Is there a short window of opportunity, early in the disease, to radically change its course and prevent joint damage?

Is inactive disease not only a worthy – but entirely possible – goal for children with JIA?

Within 6 months, according to Dr. Carol A. Wallace, findings from a small but powerful clinical trial could answer these questions, carrying the potential to completely change the treatment approach used in young patients with JIA.

"I think evidence is growing that early, aggressive therapy can fundamentally change this disease in the first year after diagnosis," she said in an interview. "And if we are looking at an opportunity for change, it behooves us to do everything possible to hit this disease early and hard."

At the annual meeting of the Pediatric Rheumatology European Society, Dr. Wallace, a pediatric rheumatologist and researcher at Seattle Children’s Hospital, spoke about what has, in the past, been considered an unrealistic goal: turning a progressive childhood rheumatologic disease into a manageable disorder, with a minimum of medical therapy and a maximum quality of life.

"People have long underestimated the burden of this disease in children," she said. "They haven’t recognized the value of completely inactive disease, or understood that having no disease activity is a truly achievable goal."

Traditionally, the JIA treatment mantra has been "start low, go slow," adding more powerful medications only as symptoms increase and joint damage becomes apparent. But in the last 10 years or so, researchers have begun to ask another question: What would happen if we hit JIA with more effective treatments, earlier on?

For some, the idea has been a hard sell.

"Yes, our most effective medications are expensive, high powered, and with potential side effects, so many physicians are afraid of using them in children," Dr. Wallace said. "But on the other hand, what would be the real value of inactive disease for these kids? What if they could have a very high quality of life – running around and playing soccer – instead of going to the doctor frequently? Getting off medication sooner could mean less overall drug exposure" than that experienced by children who are treated with less-powerful medications but who, after years of treatment, are still on drugs with active or smoldering disease.

Even administrators who guard the bottom line could be happier because of the expected savings, she said. "This way of treating might actually be more cost effective in the long run. With better quality of life and inactive disease, there could be fewer visits to the doctor, less overall utilization of health care resources, fewer joint replacements, fewer parents missing work for a child’s illness – there are a lot of purely economic ramifications from having complete disease response."

Bit by bit, the evidence supporting this idea has grown, she said at the meeting. In 2008, a retrospective study of 125 patients with at least 5 years of follow-up found that those who achieved an ACR Pedi 70 (American College of Rheumatology Pediatric 70) score by 6 months after initiation of treatment showed sustained, significantly greater improvement over the long run than did nonresponders. At the end of the study, 55% of the responders had inactive disease, compared with 17% of the nonresponders and 29% of those who responded less favorably to treatment (Ann. Rheum. Dis. 2008;67:370-4).

Imaging studies have shown that joint damage in JIA progresses fastest during the first year of the disease. A 2005 study of 13 children with newly diagnosed polyarticular JIA found progressive joint damage in six children after only 14 months. These children started disease-modifying antirheumatic drugs (DMARDs) at an average of 7.5 months after symptoms appeared. The others – who started DMARDs earlier, at an average of 1.6 months after diagnosis – had no progression (Ann. Rheum. Dis. 2005:64:491-3).

Findings from studies involving adults send a similar message: Treatment timing matters. "The evidence tells us that the disease continues to spread to additional joints, and the burden of disease becomes greater with time," Dr. Wallace said. "The adult and pediatric evidence now tells us that if we treat earlier and get it quieted down early, patients do better in the long run."

The data also confirm that treatment type matters. The most recent evidence comes from a 2010 meta-analysis of 15 randomized, controlled trials comprising 4,200 patients with rheumatoid arthritis of less than 3 years’ duration. Treatment regimens in the studies included DMARDs, a combination of tumor necrosis factor (TNF) blockers plus methotrexate, and methotrexate alone. "Both the DMARDs and the combination therapy were superior to methotrexate alone," Dr. Wallace said. Patients taking the anti-TNF and methotrexate had higher ACR responses, fewer withdrawals for inefficacy or toxicity, lower disability scores, and less erosive damage on imaging (Rheumatology 2010;49:91-8).

Again, childhood data show similar findings. A study reported at the 2009 ACR annual meeting randomized 60 DMARD-naive JIA patients with just 6 weeks’ disease duration to methotrexate, methotrexate plus infliximab, or a combo of methotrexate, sulfasalazine, and hydroxychloroquine. At 6 months, an ACR Pedi 75 response occurred in 100% of the double therapy group, 65% of the triple therapy group, and 10% of the methotrexate-only group. By 54 weeks, 68% of the double therapy, 40% of the triple therapy, and 25% of the methotrexate groups had inactive disease.

All of these encouraging data lead to the TREAT (Trial of Early Aggressive Therapy) in JIA trial, the results of which Dr. Carol Wallace is eagerly awaiting. The yearlong study randomized 85 children with polyarticular or extended oligoarticular JIA to one of two aggressive treatment regimens. Because all of the subjects had a disease duration of less than 12 months, TREAT may provide answers about optimal timing as well as optimal therapy.

The study is being conducted by CARRA (Childhood Arthritis and Rheumatology Research Alliance). Founded by researchers, CARRA conducts investigator-initiated clinical trials not only for JIA, but also for other childhood rheumatic diseases (www.carragroup.org). CARRA now comprises 92 pediatric rheumatology centers and more than 300 clinician members all over North America.

TREAT was conducted at 15 CARRA sites. Both weekly treatment arms included subcutaneous methotrexate at 0.5 mg/kg. Group A also received placebo etanercept, folate, NSAIDs as necessary, and a placebo prednisone taper. Group B received, in addition to methotrexate, weekly subcutaneous injections of etanercept at 0.8 mg/kg; folate; NSAIDs as needed; and a 4-month prednisone taper that started at 0.5 mg/kg.

The study’s primary end point is the rate of inactive disease at 6 months. Secondary end points include the rate of ACR Pedi 70 by 4 months; clinical remission on medication by 12 months; safety of the treatment, and MRI of the knee to show potential biologic changes associated with active and inactive disease.

The children’s mean age was 11 years and their mean disease duration was just over 4 months. They had a mean of 22 active joints and a mean erythrocyte sedimentation rate of 37. Their mean Physician Global Assessment score was nearly 7. Most of the children (69%) were positive for antinuclear antibodies; 36% were rheumatoid factor positive.

The last subject visits have just occurred, and so full data analysis has not been completed. Dr. Wallace said that 77 patients finished out the pivotal first 6 months of the trial. At that point, those who achieved a state of inactive disease continued on their assigned treatment arm until the end of the trial, or until they had a flare. Those who still had active disease at 6 months could opt for up to 6 months of open-label etanercept plus methotrexate and a prednisone taper, or up to two intra-articular injections while continuing on their blinded treatment. If they then experienced a flare, they discontinued the trial.

By the end of October, 67 patients (77%) had completed 12 months of the trial. Dr. Wallace and her coinvestigators expect to release the results in the first quarter of 2011.

Despite its relatively small size, she said, TREAT could be practice transforming. "Whatever the result, we plan to deploy this treatment as quickly as we can in clinical practice. That’s actually the beauty of the CARRA network. We can, through our members, make a standard of care based on data. And that’s what this study is all about – finding evidence. We must continue to look for evidence that supports the best way to treat JIA."

Although Amgen supplied the etanercept for TREAT, the study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. Dr. Wallace has no financial disclosures with regard to the study.

Can early, aggressive treatment stop the often-relentless march of juvenile idiopathic arthritis?

Is there a short window of opportunity, early in the disease, to radically change its course and prevent joint damage?

Is inactive disease not only a worthy – but entirely possible – goal for children with JIA?

Within 6 months, according to Dr. Carol A. Wallace, findings from a small but powerful clinical trial could answer these questions, carrying the potential to completely change the treatment approach used in young patients with JIA.

"I think evidence is growing that early, aggressive therapy can fundamentally change this disease in the first year after diagnosis," she said in an interview. "And if we are looking at an opportunity for change, it behooves us to do everything possible to hit this disease early and hard."

At the annual meeting of the Pediatric Rheumatology European Society, Dr. Wallace, a pediatric rheumatologist and researcher at Seattle Children’s Hospital, spoke about what has, in the past, been considered an unrealistic goal: turning a progressive childhood rheumatologic disease into a manageable disorder, with a minimum of medical therapy and a maximum quality of life.

"People have long underestimated the burden of this disease in children," she said. "They haven’t recognized the value of completely inactive disease, or understood that having no disease activity is a truly achievable goal."

Traditionally, the JIA treatment mantra has been "start low, go slow," adding more powerful medications only as symptoms increase and joint damage becomes apparent. But in the last 10 years or so, researchers have begun to ask another question: What would happen if we hit JIA with more effective treatments, earlier on?

For some, the idea has been a hard sell.

"Yes, our most effective medications are expensive, high powered, and with potential side effects, so many physicians are afraid of using them in children," Dr. Wallace said. "But on the other hand, what would be the real value of inactive disease for these kids? What if they could have a very high quality of life – running around and playing soccer – instead of going to the doctor frequently? Getting off medication sooner could mean less overall drug exposure" than that experienced by children who are treated with less-powerful medications but who, after years of treatment, are still on drugs with active or smoldering disease.

Even administrators who guard the bottom line could be happier because of the expected savings, she said. "This way of treating might actually be more cost effective in the long run. With better quality of life and inactive disease, there could be fewer visits to the doctor, less overall utilization of health care resources, fewer joint replacements, fewer parents missing work for a child’s illness – there are a lot of purely economic ramifications from having complete disease response."

Bit by bit, the evidence supporting this idea has grown, she said at the meeting. In 2008, a retrospective study of 125 patients with at least 5 years of follow-up found that those who achieved an ACR Pedi 70 (American College of Rheumatology Pediatric 70) score by 6 months after initiation of treatment showed sustained, significantly greater improvement over the long run than did nonresponders. At the end of the study, 55% of the responders had inactive disease, compared with 17% of the nonresponders and 29% of those who responded less favorably to treatment (Ann. Rheum. Dis. 2008;67:370-4).

Imaging studies have shown that joint damage in JIA progresses fastest during the first year of the disease. A 2005 study of 13 children with newly diagnosed polyarticular JIA found progressive joint damage in six children after only 14 months. These children started disease-modifying antirheumatic drugs (DMARDs) at an average of 7.5 months after symptoms appeared. The others – who started DMARDs earlier, at an average of 1.6 months after diagnosis – had no progression (Ann. Rheum. Dis. 2005:64:491-3).

Findings from studies involving adults send a similar message: Treatment timing matters. "The evidence tells us that the disease continues to spread to additional joints, and the burden of disease becomes greater with time," Dr. Wallace said. "The adult and pediatric evidence now tells us that if we treat earlier and get it quieted down early, patients do better in the long run."

The data also confirm that treatment type matters. The most recent evidence comes from a 2010 meta-analysis of 15 randomized, controlled trials comprising 4,200 patients with rheumatoid arthritis of less than 3 years’ duration. Treatment regimens in the studies included DMARDs, a combination of tumor necrosis factor (TNF) blockers plus methotrexate, and methotrexate alone. "Both the DMARDs and the combination therapy were superior to methotrexate alone," Dr. Wallace said. Patients taking the anti-TNF and methotrexate had higher ACR responses, fewer withdrawals for inefficacy or toxicity, lower disability scores, and less erosive damage on imaging (Rheumatology 2010;49:91-8).

Again, childhood data show similar findings. A study reported at the 2009 ACR annual meeting randomized 60 DMARD-naive JIA patients with just 6 weeks’ disease duration to methotrexate, methotrexate plus infliximab, or a combo of methotrexate, sulfasalazine, and hydroxychloroquine. At 6 months, an ACR Pedi 75 response occurred in 100% of the double therapy group, 65% of the triple therapy group, and 10% of the methotrexate-only group. By 54 weeks, 68% of the double therapy, 40% of the triple therapy, and 25% of the methotrexate groups had inactive disease.

All of these encouraging data lead to the TREAT (Trial of Early Aggressive Therapy) in JIA trial, the results of which Dr. Carol Wallace is eagerly awaiting. The yearlong study randomized 85 children with polyarticular or extended oligoarticular JIA to one of two aggressive treatment regimens. Because all of the subjects had a disease duration of less than 12 months, TREAT may provide answers about optimal timing as well as optimal therapy.

The study is being conducted by CARRA (Childhood Arthritis and Rheumatology Research Alliance). Founded by researchers, CARRA conducts investigator-initiated clinical trials not only for JIA, but also for other childhood rheumatic diseases (www.carragroup.org). CARRA now comprises 92 pediatric rheumatology centers and more than 300 clinician members all over North America.

TREAT was conducted at 15 CARRA sites. Both weekly treatment arms included subcutaneous methotrexate at 0.5 mg/kg. Group A also received placebo etanercept, folate, NSAIDs as necessary, and a placebo prednisone taper. Group B received, in addition to methotrexate, weekly subcutaneous injections of etanercept at 0.8 mg/kg; folate; NSAIDs as needed; and a 4-month prednisone taper that started at 0.5 mg/kg.

The study’s primary end point is the rate of inactive disease at 6 months. Secondary end points include the rate of ACR Pedi 70 by 4 months; clinical remission on medication by 12 months; safety of the treatment, and MRI of the knee to show potential biologic changes associated with active and inactive disease.

The children’s mean age was 11 years and their mean disease duration was just over 4 months. They had a mean of 22 active joints and a mean erythrocyte sedimentation rate of 37. Their mean Physician Global Assessment score was nearly 7. Most of the children (69%) were positive for antinuclear antibodies; 36% were rheumatoid factor positive.

The last subject visits have just occurred, and so full data analysis has not been completed. Dr. Wallace said that 77 patients finished out the pivotal first 6 months of the trial. At that point, those who achieved a state of inactive disease continued on their assigned treatment arm until the end of the trial, or until they had a flare. Those who still had active disease at 6 months could opt for up to 6 months of open-label etanercept plus methotrexate and a prednisone taper, or up to two intra-articular injections while continuing on their blinded treatment. If they then experienced a flare, they discontinued the trial.

By the end of October, 67 patients (77%) had completed 12 months of the trial. Dr. Wallace and her coinvestigators expect to release the results in the first quarter of 2011.

Despite its relatively small size, she said, TREAT could be practice transforming. "Whatever the result, we plan to deploy this treatment as quickly as we can in clinical practice. That’s actually the beauty of the CARRA network. We can, through our members, make a standard of care based on data. And that’s what this study is all about – finding evidence. We must continue to look for evidence that supports the best way to treat JIA."

Although Amgen supplied the etanercept for TREAT, the study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. Dr. Wallace has no financial disclosures with regard to the study.