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Longer Treatment of JIA in Remission May Not Reduce Relapses

Laurie Barclay, MD

Authors and Disclosures

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April 6, 2010 ( UPDATED April 7, 2010 ) — For patients with juvenile

idiopathic arthritis (JIA) in remission, withdrawal of methotrexate treatment

for 12 months vs 6 months does not lower the relapse rate, according to the

results of a prospective, open, multicenter, randomized controlled trial

reported in the April 7 issue of the Journal of the American Medical

Association.

" Novel therapies have improved the remission rate in chronic inflammatory

disorders including ...JIA, " write Dirk Foell, MD, from the University of

Muenster in Muenster, Germany, and colleagues from the Paediatric Rheumatology

International Trials Organization (PRINTO). " Therefore, strategies of tapering

therapy and reliable parameters for detecting subclinical inflammation have now

become challenging questions. "

Medication Withdrawal and Relapses

The goals of this medication withdrawal study were to determine whether longer

methotrexate treatment during remission of JIA would prevent flares after

withdrawal of medication and whether specific biomarkers could predict which

patients would experience flares.

Between February 2005 and June 2006, a total of 364 patients with JIA were

recruited at 61 centers in 29 countries. Median age was 11.0 years. Participants

were enrolled when clinical remission was first confirmed while continuing

medication. Levels of the phagocyte activation marker myeloid-related proteins 8

and 14 heterocomplex (MRP8/14) were determined when treatment was withdrawn.

Patients were randomly assigned to continue with methotrexate treatment therapy

for either 6 months (group 1 [n = 183]) or for 12 months (group 2 [n = 181])

after remission was induced.

The main study endpoint was relapse rate in the 2 treatment groups, and the

secondary endpoint was time to relapse. The investigators also determined the

prognostic accuracy of MRP8/14 concentrations in the risk for flares in a

prespecified cohort analysis. Median follow-up duration after inclusion was 34.2

months in group 1 and 34.3 months in group 2.

Relapse within 24 months after study enrollment occurred in 98 (56.7%) of 183

patients in group 1 and in 94 (55.6%) of 181 patients in group 2, based on

intent-to-treat analysis, yielding an odds ratio for group 1 vs group 2 of 1.02

(95% confidence interval [CI], 0.82 - 1.27; P = .86). Median relapse-free

interval after inclusion was 21.0 months in group 1 vs 23.0 months in group 2,

yielding a hazard ratio for group 1 vs group 2 of 1.07 (95% CI, 0.82 - 1.41; P =

..61).

Compared with patients maintaining stable remission, patients who subsequently

experienced flares had significantly higher levels of MRP8/14 during remission

(median, 715 ng/mL [iQR, 320 - 1110 ng/mL] vs 400 ng/mL [iQR, 220 - 800 ng/mL];

P = .003). Low MRP8/14 levels were associated with a low risk for flares within

the next 3 months after testing. Area under the receiver operating

characteristic curve was 0.76 (95% CI, 0.62 - 0.90).

On the basis of these findings, the study authors noted that in patients with

JIA in remission, a 12-month vs a 6-month withdrawal of methotrexate did not

reduce the relapse rate, and higher MRP8/14 concentrations were associated with

a risk for relapse after discontinuation of methotrexate.

No Benefit in Continuing Methotrexate

" There is no benefit of continuing methotrexate for longer than 6 months of

inactive disease, " Philip J. Hashkes, MD, MSc, head of the Pediatric

Rheumatology Unit at Shaare Zedek Medical Center in Jerusalem, Israel, told

Medscape Rheumatology when asked for independent comment.

" High levels of biomarkers (in this case, MRP8/14) during periods of inactive

clinical disease may be a sign of subclinical inflammation and predict patients

more likely to relapse — the higher the level, the greater risk of flare in

the short-term. Although not fully [addressed] in the study, physicians should

be more cautious in discontinuing methotrexate in patients with very high

levels. "

Study Limitations and Strengths

Limitations of this study include inability to determine total length of

remission in patients who did not have a flare during the study, possible

confounding by subtype, and lack of generalizability of biomarker data to all

patients undergoing other therapies. In addition, the secondary outcome of the

biomarker findings is based on a cohort analysis.

" MRP8/14 testing is not widely performed and is not available in most clinical

settings, " Dr. Hashkes said. " It is still unclear what instructions physicians

should give to patients with high levels of MRP8/14 regarding continuing

methotrexate. The study only examined one method of methotrexate weaning

(complete discontinuation of methotrexate at once) and tested MRP8/14 only once

at methotrexate discontinuation; thus, serial measurements were not available

later when patients actually relapsed (or did not relapse). "

Strengths of the study cited by Dr. Hashkes include the large size of the

cohort; random assignment of when to stop methotrexate; and all subtypes of JIA

studied, with no differences found among the various subtypes.

The study authors pointed out that patients with chronic inflammatory diseases

should be stratified to ensure that the intensity of treatment is adjusted to

the patients' individual needs.

Future Research

Regarding additional research, Dr. Hashkes recommended the following steps:

Examine whether the MRP8/14 biomarker truly correlates with subclinical

inflammation (eg, by performing magnetic resonance imaging studies of previously

active joints to search for signs of arthritis).

Serially test MRP8/14 levels to observe if, within an individual patient, a

change in the biomarker level correlates with disease flare.

Examine if the MRP8/14 biomarker level is also a predictor of flare in

discontinuation of biologic modifiers.

Search for other biomarkers more easily available in most clinical settings.

Grants from the non-for-profit organizations PRINTO and the " Deutsche

Rheuma-Liga " supported this study. Wyeth Pharmaceuticals funded the patients'

insurance in Germany. The study authors and Dr. Hashkes have disclosed no

relevant financial relationships.

JAMA. 2010;303:1266-1273.

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Authors and Disclosures

Journalist

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial

relationships.