Aggressive Combination Therapy Helps Children with Juvenile Idiopathic Arthritis Achieve Inactive Disease Faster

Released: 18-Oct-2013 11:20 AM EDT
Embargo expired: 26-Oct-2013 4:30 PM EDT
Source Newsroom: American College of Rheumatology (ACR)
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Newswise — SAN DIEGO — Children with juvenile idiopathic arthritis who receive early, aggressive therapy with a combination of medications achieve clinical inactive disease status faster than they would with less aggressive therapy, according to new research presented this week at the American College of Rheumatology Annual Meeting in San Diego.

Juvenile idiopathic arthritis, commonly called JIA or juvenile rheumatoid arthritis, is a term for several types of arthritis, all involving chronic (long-term) joint inflammation. This inflammation begins before patients reach the age of 16, and symptoms last from six weeks to three months to be called chronic. JIA may involve one or many joints, and cause other symptoms such as fevers, rash and/or eye inflammation.

It is not known what causes the immune system to malfunction in JIA. These conditions are not considered hereditary and rarely involve more than one family member. Research suggests that some individuals may have a genetic tendency to develop JIA, but develop the condition only after exposure to an infection or other unknown trigger. Dietary and emotional factors do not appear to play a role in the development of JIA. These disorders can affect children at any age, although rarely in the first six months of life. It is estimated that around 300,000 children in the United States have been diagnosed with JIA.

Researchers at the Seattle Children’s Hospital and Research Institute and other children’s hospitals and research centers throughout the United States analyzed data from a double-blind, randomized, placebo- controlled study: the Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis. The study compared two aggressive therapy approaches for treating JIA in 85 patients ages two to 17 to determine which regimen would help the children achieve clinical inactive disease within six months. They also looked at the possibility of more aggressive therapy helping children achieve clinical remission of their disease, measured as six months of continuous clinical inactive disease.

“The purpose of this study was to identify the predictors for achievement of and sustainability of clinical inactive disease for children with polyarticular JIA treated with early, aggressive therapy,” says Carol Wallace, MD; director; in the study. “This is the first clinical trial to use inactive disease and remission of disease as the outcomes for the study, and to compare two aggressive treatment approaches.”

Participants had polyarticular JIA for less than 12 months and were randomly assigned to two treatment approaches. Forty-two patients were given a more aggressive, combination therapy of methotrexate 0.5 mg/kg /wk injection, etanercept 0.8 mg/kg/wk and prednisolone 0.5 mg/kg/d tapered to zero by 17 weeks. A second group of 43 patients were given a less aggressive regimen of methotrexate 0.5 mg/kg/wk injection and placebo etanercept and prednisolone. Patients were tested to determine if they had achieved clinical inactive disease according to the Wallace Criteria at intervals of one, two, four, five, six, seven, eight, 10 and 12 months. Participants who failed to achieve either ACR Pedi 70 after four months, or clinical inactive disease after six months were switched to the open-label, more aggressive therapy of methotrexate, etanercept and prednisolone.

In the most aggressive therapy group, 30 participants achieved clinical inactive disease at least once, compared to 28 participants starting in the less aggressive therapy group, however 17 of those 28 only achieved clinical inactive disease after switching to the open-label more aggressive combination therapy. The median number of days on therapy before achieving clinical inactive disease was 168.5 for the combination therapy group and 192 for the less aggressive therapy group. Participants in the combination therapy group spent a median of 139.5 days of follow-up with clinical inactive disease, compared to a median of 79 days of follow-up for those in the less aggressive therapy group.

The researchers concluded that aggressive therapy given early in the course of JIA helps a large proportion of patients achieve clinical inactive disease within 12 months. Also, a combination therapy of an anti-tumor necrosis factor agent, methotrexate and prednisolone helps patients achieve sustainable clinical inactive disease better than methotrexate alone.

“This study reinforces the importance of treating JIA early and aggressively, in order to achieve and sustain clinical inactive disease and clinical remission on medications,” Dr. Wallace says.

Patients should talk to their rheumatologists to determine their best course of treatment.

The American College of Rheumatology is an international professional medical society that represents more than 9,000 rheumatologists and rheumatology health professionals around the world. Its mission is to advance rheumatology. The ACR/ARHP Annual Meeting is the premier meeting in rheumatology. For more information about the meeting, visit http://www.acrannualmeeting.org/ or join the conversation on Twitter by using the official hashtag: #ACR13

Editor’s Notes: Dr. Wallace will present this research during the ACR Annual Meeting at the San Diego Convention Center at 2:30 PM on Sunday, October 27 in Room 28 D. Dr. Wallace will be available for media questions and briefing at 8:30 am Tuesday, October 29 in the on-site press conference room, 27 AB.

Funding sources for this study include the National Institute for Arthritis and Musculoskeletal and Skin Diseases, and the Howe Endowment for Juvenile Idiopathic Arthritis Research.

Abstract Number: 790

Predictors and Sustainability Of Clinical Inactive Disease In Polyarticular Juvenile Idiopathic Arthritis Given Aggressive Therapy Very Early In The Disease Course

Carol A. Wallace1, Edward H. Giannini2, Steven J. Spalding3, Philip J. Hashkes4, Kathleen M. O'Neil5, Andrew S. Zeft3, Ilona S. Szer6, Sarah Ringold7, Hermine I. Brunner2, Laura E. Schanberg8, Robert P. Sundel9, Diana Milojevic10, Marilynn G. Punaro11, Peter Chira12, Beth S. Gottlieb13, Gloria C. Higgins14, Norman T. Ilowite15, Yukiko Kimura16, Anne Johnson2, Bin Huang17 and Daniel J. Lovell2, 1Seattle Childrens Hosp & Research Institute, Seattle, WA, 2Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 3The Cleveland Clinic, Cleveland, OH, 4Shaare Zedek Medical Center, Jerusalem, Israel, 5Riley Hospital for Children, Indianapolis, IN, 6Rady Childrens Hosp San Diego, San Diego,CA, 7Seattle Children's Hospital, Seattle, WA, 8Duke University Medical Center, Durham, NC, 9Boston Children's Hospital and Harvard Medical School, Boston, MA, 10University of California, San Francisco, San Francisco, CA, 11Texas Scottish Rite Hospital, Dallas, TX, 12Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, 13Cohen Children's Medical Center of New York, New Hyde Park, NY, 14Nationwide Childrens Hosp, Columbus, OH, 15The Children's Hospital at Montefiore, Bronx, NY, 16Joseph M Sanzari Children’s Hospital, Hackensack University Medical Center, Hackensack,NJ, 17Cincinnati Children's Hospital Medical Center/University of Cincinnati School of Medicine,Cincinnati, OH

Background/Purpose: The double-blind, randomized placebo-controlled Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis (TREAT) compared the ability of 2 aggressive treatment regimens to produce clinical inactive disease (CID) within 6 mos of starting therapy. An exploratory phase lasting up to 1 year from baseline determined if patients could achieve CID after switching to the more aggressive treatment arm (M-E-P: etanercept 0.8 mg/kg/wk, MTX 0.5 mg/kg/wk given subcutaneously, prednisolone 0.5 mg/kg/d tapered to zero by 17 wks) from the less aggressive arm (MTX: MTX as in the M-E-P Arm, placebo prednisolone, placebo etanercept ), and achieve clinical remission on medication (CRM; 6 continuous mos of CID). The purposes of this analysis were to determine lapsed time on-therapy to the first occurrence, and sustainability of CID and if predictors of CID exist.

Methods: Eighty-five patients aged 2-17 yrs with active RF (+) or (-) polyarticular JIA (poly-JIA) less than 12 mos in duration (median 4.2 mos) were randomized to either M-E-P (N=42) or MTX (N=43) and assessed for CID using the Wallace Criteria at mos 1, 2, 4, 5, 6, 7, 8, 10 and 12 mos or discontinuation. Patients in either group who failed to achieve an ACR Pedi 70 at 4 mos, or CID at 6 mos were switched to open-label M-E-P for the remainder of the study. Descriptive measures, the Mann- Whitney U and Fisher’s Exact tests were the chief statistical methods.

Results: CID was observed at least once in 30 (71%) of those who started on M-E-P and in 28 (65%) of MTX starts (17 of these 28 achieved CID only after switching to open-label M-E-P). Median number of days on aggressive therapy until the first occurrence of CID was 168.5 and 192 for those who started M-E-P and MTX groups respectively. M-E-P starts spent a median of 139.5 (42%) days of follow-up with CID, compared to a median of 79 (24%) days for MTX starts (p=0.016). M-E-P starts had CID at 117 of 347 (34%) follow-up visits while MTX starts had CID at 81 of 337 (24%) visits. When data were combined from the blinded and open-label (all patients receiving M-E-P) phases, CID was observed at 154 of 481 (32%) visits by patients on M-E-P, compared to 43 of 203 (21%) visits while receiving MTX alone.

Baseline characteristics were not statistically predictive of CID except for disease duration prior to enrollment. Patients with duration ≤3 mos at enrollment had CID at a median of 40% of visits, while those with disease >3 mos had CID for a median of only 11% of visits (p<0.0001).

Among 49 patients who achieved an ACR Pedi 70 at 4 mos, 42 (86%) attained CID, compared to 16 of 36 (44%) who failed to achieve the early response (p=0.0001). All 12 patients (9 M-E-P and 3 MTX) who achieved CRM met the ACR Pedi 70 at 4 mos.

Conclusion: Aggressive therapy given early in the disease course of poly-JIA results in a large proportion of patients achieving CID within 12 mos. There is a tendency for a combination of an anti-TNF agent, MTX and prednisolone to produce more sustainable CID than does high dose MTX monotherapy. A short disease duration prior to start of aggressive therapy and attainment of an ACR Pedi 70 by 4 mos are significant predictors of achieving sustained CID.

Disclosures:
C. A. Wallace, Amgen, 2, Pfizer Inc, 2, Novartis Pharmaceutical Corporation, 5
E. H. Giannini, None S. J. Spalding, None P. J. Hashkes, None K. M. O'Neil, UCB, 5
A. S. Zeft, Pfizer Inc, 1


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