RESEARCH - Enbrel effecctive in about half of refractory SOJRA cases

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Etanercept effective in about half of refractory SOJRA cases

Rheumawire

May 17, 2005

Zosia Chustecka

Hackensack, NJ - About half the children with refractory systemic onset

juvenile rheumatoid arthritis (SOJRA) treated with the TNF-antagonist

etanercept (Enbrel, Immunex and Wyeth) appear to respond, a survey of US

pediatric rheumatologists has found [1]. This finding, together with

preliminary reports of successful treatment with the interleukin-6 (IL-6)

blocker MRA (still in clinical trials; Roche and Chugai) and the

interleukin-1 antagonist anakinra (Kineret, Amgen), suggest that TNF may not

be the driving proinflammatory cytokine in this disease and that TNF

blockade may not be the optimal therapeutic approach.

Although SOJRA is the least common form of juvenile rheumatoid arthritis, it

is often the most challenging to manage, comments an accompanying editorial

in the May 2005 issue of the Journal of Rheumatology [2]. Between 25% and

35% of systemic patients develop severe erosive arthritis and

extra-articular complications, including life-threatening serositis or

macrophage activation syndrome (MAS). However, it is difficult to identify

on onset those patients with poor prognoses, making treatment decisions

challenging, it comments. At present, etanercept is a third-line agent in

the standard care of SOJRA, following methotrexate as second-line after

traditional treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and

corticosteroids.

Disease flares seen even in good responders

The survey was conducted by Dr Yukiko Kimura (ph Sanzari Children's

Hospital, Hackensack University Medical Center, NJ), working with

researchers at other US centers. The team sent out a standardized

questionnaire to 122 pediatric rheumatologists in the US, although less than

a quarter replied, supplying information on 100 children with SOJRA, of whom

82 had analyzable data.

Of the 82 patients, 48 (59%) were female, with a mean age at disease onset

of 4.25+3.73 years (range 0.25-17). The authors note that the patient who

was 17 at disease onset would be categorized as adult-onset Still's disease

rather than SOJRA, but " because the 2 diseases are virtually identical aside

from the differences in ages at onset, we included him in the analysis. " The

mean disease duration before initiation of etanercept was 5.18+4.2 years,

and the mean duration of etanercept treatment was 24.8+12.3 months. All

patients initially received the standard dose of 0.4 mg/kg twice weekly

subcutaneously, but 29 patients went on to receive higher doses

subsequently.

The majority of patients (54%) had poor or limited responses, and flares

occurred in 45% of all patients, the authors report. Good or excellent

responses were seen in 46%, and most of them were able to discontinue

corticosteroids, which is " an important finding in these patients with

refractory disease, " the authors comment. However, even among the

responders, more than one quarter had flares while on etanercept therapy.

Also, the drug did not prevent the occurrence of MAS during a disease flare

in 2 patients, 1 of whom had initially been an excellent responder, they

note. Etanercept was not thought to be the cause of MAS, but the fact that 2

children developed it " underscores the failure of etanercept to prevent

disease flares in patients. "

Kimura et al comment that although the results are limited by the

retrospective design of the study, which subjects it to ascertainment bias,

they are consistent with other recently published studies, such as that of

Quartier et al, who found that SOJRA patients were less responsive to

etanercept and more likely to experience flares compared with patients with

other types of JRA [3]. " TNF blockade may not be the optimal therapeutic

approach for children with treatment-resistant SOJRA, " they conclude.

New approaches show promise

The accompanying editorial reviews growing evidence suggesting that in

active SOJRA the driving proinflammatory cytokine is IL-6 rather than TNF.

It highlights clinical results with the anti-IL-6 receptor monoclonal

antibody (MRA), including a small open-label trial that was " very

encouraging, with complete remission in 10 out of 11 patients [4]. " There

have also been anecdotal reports about " excellent response " with the

interleukin-1 antagonist anakinra in SOJRA, including many patients who had

failed on etanercept. Both of these approaches have been reported previously

by rheumawire.

Clinical trials in SOJRA with both products are expected to start shortly,

the editorial notes. The outcomes of these future biological-therapy trials

may influence how the current findings on etanercept are viewed, it adds: as

a glass that is half full (nearly half the children respond) or half empty

(only about half of the children respond).

Kimura commented to rheumawire: " Treatments aimed at IL-1 and IL-6

inhibition show great promise in the treatment of SOJRA. There have been

several case reports in the literature regarding the efficacy of anakinra in

patients who have failed other agents. The reports from Japan regarding MRA

(anti-IL-6) are also quite exciting, and so we eagerly await the results of

a larger study from Japan, as well as hopefully clinical trials here in the

US. " He does not have any personal experience with anti-IL-6 but has used

anakinra and says: " While there are patients with SOJRA who respond nicely

to it, there are others who do not respond. So while there is great

potential for these biologic therapies, we will need to await results of

larger randomized trials testing these therapies in SOJRA before we will

have a true sense of their efficacy. "

As for what to use currently, Kimura comments: " The results of our paper

show that about half of the patients responded to etanercept, so it is

certainly worth trying in patients who have failed other therapies. Anakinra

certainly has potential in this disease, and because there seems to be

improved efficacy of this biologic compared with etanercept, there are

pediatric rheumatologists who would try this medication before trying

etanercept. "

Sources

a. Kimura Y, Pinho P, Walco G, et al. Etanercept treatment in

patients with refractory systemic onset juvenile rheumatoid arthritis. J

Rheumatol 2005; 32:935-942.

b. Eberhard BA and Ilowite NT. Response of systemic onset

juvenile rheumatoid arthritis to etanercept: is the glass half full or half

empty? J Rheumatol 2005; 32:935-942.

c. Quartier P, Taupin P, Bourdeaut F, et al. Efficacy of

etanercept for the treatment of juvenile idiopathic arthritis according to

the onset type. Arthritis Rheum 2003; 48:1093-1101.

d. Yokota S, Miyamae T, Imagawa T, et al. Therapeutic

efficacy of humanized recombinant anti-interleukin-6 receptor antibody in

children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum

2005; 52:818-825.

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