New Treatment Advances for Juvenile Idiopathic Arthritis

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New Treatment Advances for Juvenile Idiopathic Arthritis CME

Tadej Avcin, MD, PhD

http://www.medscape.com/viewarticle/567669?src=mp

Introduction

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of chronic

idiopathic arthritides with an onset in children who are younger than 16

years. It is the most frequent rheumatic disease encountered in children

that results in a destructive phenotype manifested by progressive joint and

organ damage -- without optimal and early treatment. The recent American

College of Rheumatology (ACR) 2007 Annual Meeting, held in Boston,

Massachusetts, in November 2007, provided a comprehensive update on current

and developing treatment for patients with JIA. Biologic agents that target

specific cytokine abnormalities are being increasingly investigated in

pediatric rheumatic diseases, and several clinical trials are currently

under way that will provide new information in regard to the optimal

treatment of JIA patients and hopefully will improve long-term outcome of

the disease. New data concerning biologic agents were extensively presented

at the ACR 2007 meeting, and key points from relevant presentations are

discussed in this report.

Management of Complications of Systemic JIA

An overview of the use of, and complications of, new therapeutics in the

management of systemic JIA was summarized in a State-of-the-Art Lecture,[1]

which focused on the distinctive extra-articular manifestations of systemic

JIA and discussed differential diagnosis of febrile syndromes of childhood,

including malignancy, infections, autoimmune connective tissue diseases,

vasculitis (particularly Kawasaki disease), and autoinflammatory syndromes.

Important complications of systemic JIA were presented, including severe

joint damage, poor functional outcome, growth delay, osteoporosis,

macrophage activation syndrome (MAS), amyloidosis, and increased mortality.

The lecture emphasized early predictors of severe complications of systemic

JIA, such as serum levels of CD163 and soluble interleukin (IL)-2 receptor,

as diagnostic markers for MAS. This issue also was addressed in the study of

gene expression profiles in systemic JIA presented by Fall and

colleagues,[2] in which a distinct pattern of gene expression was identified

in a subgroup of systemic JIA patients with subclinical MAS.

Systemic JIA is one of the most challenging forms of JIA to treat, and the

approach to its management must be a coordinated one that includes

management of extra-articular features and articular disease.[1] Management

of the chronic systemic arthritis follows the same principles of management

of arthritis in other forms of JIA; however, use of intra-articular

corticosteroid injections and methotrexate is generally less effective than

in other JIA subtypes. Newer therapies for systemic JIA, including antitumor

necrosis factor (anti-TNF) agents, anti-IL-1, anti-IL-6, thalidomide,

abatacept, and autologous hematopoietic stem cell transplantation.[1]

Update on Biologic Therapies

TNF Inhibitors

Etanercept is a recombinant form of the human p75 TNF receptor fusion

protein and was the first biologic agent studied for JIA in clinical trials.

Reiff and colleagues[3] presented safety data on over 8 years of continuous

etanercept therapy in patients with polyarticular JIA. A total of 58

patients were involved in a multicenter, open-label extension study for a

total of 318 patient-years of etanercept exposure. Complete data of 8 years

of continuous etanercept therapy were available in 16 patients, whereas 38

patients withdrew because of patient/guardian refusal, suboptimal treatment

response, adverse events, or physician decision. At 8 years, affected joints

were resolved in 36% of patients. Sixteen patients experienced 39 severe

adverse events during the original randomized controlled trial and

open-label extension period, and the rate of severe adverse events did not

increase with continuous use of etanercept. It was very encouraging that no

patients died and that no cases of tuberculosis, opportunistic infections,

demyelinating disorders, or malignancies were reported. Updated safety data

are of great relevance for the treating physician, and it appears that

etanercept is safe and effective as a long-term, continuous therapy for

polyarticular JIA.

Foeldvari and colleagues[4] presented data on the efficacy and tolerability

of etanercept in 107 patients with enthesitis-related arthritis who have

been included in the German Etanercept Registry. The mean duration of

therapy was 1.3 years, and significant improvements were reported in several

disease activity parameters, including decreased number of active joints,

decreased duration of morning stiffness, and decreased scores of

patient/guardian and physician global assessments of disease activity.

Twelve patients were successfully weaned off the etanercept with continued

disease remission, and only 1 life-threatening side effect was reported.

Additionally, Tse and coworkers[5] presented the long-term outcome data on

12 patients with refractory juvenile spondyloarthropathy/enthesitis-related

arthritis who were treated with anti-TNF agents for more than 2 years. Five

patients were treated with infliximab, 4 with etanercept, and 3 with

infliximab followed by etanercept. All patients in this small uncontrolled

study exhibited clinical and laboratory improvement as early as 6 weeks, and

most achieved complete remission by 6 months, which was maintained during

the follow-up period. Similar to other uncontrolled studies, this one must

be interpreted with caution, but it does suggest efficacy of anti-TNF

therapy in patients with refractory enthesitis-related arthritis.

Adalimumab is a recombinant human monoclonal antibody that binds

specifically to TNF-alpha and blocks its interaction with the p55 and p75

cell-surface TNF receptors. Lovell and colleagues[6] presented the efficacy

and safety results from a multicenter, phase 3, randomized withdrawal study

of 171 patients with polyarticular JIA. In a 16-week, open-label period all

patients received adalimumab 24 mg/m2 body surface area given as a

subcutaneous injection every other week. Patients were categorized as those

taking adalimumab with methotrexate (N = 85) or without methotrexate (N =

86). At the end of the open phase study, 83% of patients achieved an ACR

Pediatric 30 (ACR Pedi 30) response and were randomized to receive either

adalimumab or placebo for 32 weeks. In the double-blind phase, patients

receiving adalimumab had significantly fewer disease flares than those on

placebo. Disease flare rates in the groups of patients taking adalimumab and

methotrexate were 37%, adalimumab 43%, methotrexate 65%, and placebo 71%.

Marked improvements in disease activity and severity were maintained through

2 years of treatment in the open-label extension study. Adalimumab was

generally well tolerated, and no tuberculosis, opportunistic infections, or

malignancy were reported. Overall, the response rates in this study were

quite high, and the results suggest efficacy and safety of adalimumab either

as a monotherapy or in combination with methotrexate for children with

polyarticular JIA.

IL-1 Inhibition

Rilonacept (IL-1 Trap) is a long-acting IL-1 blocker that is likely to be a

more efficient inhibitor in vivo of IL-1 than anakinra. At the ACR meeting,

preliminary evidence for sustained efficacy of rilonacept in systemic JIA

was presented.[7] Twenty-four patients with active systemic JIA were

enrolled in this small phase 2 study and received -- during the initial

double-blind phase -- weekly 2.2 mg/kg or 4.4 mg/kg IL-1 Trap or placebo

subcutaneously for 4 weeks. Open-label extension with dose escalation of

rilonacept up to 4.4 mg/kg is ongoing.

Results of the 4-week, double-blind period showed that percentages of

improvement measured by the adapted ACR JIA core set (including also fever

and rash within preceding 2 weeks) were similar in the placebo group and in

the patients receiving the 2.2-mg/kg or 4.4-mg/kg weekly dose of rilonacept.

Despite lack of impressive average response, some isolated patients showed

obvious response, and with additional microarray analysis of genes

downregulated by rilonacept, they were able to demonstrate clear

heterogeneity of the systemic JIA patients included in the study cohort.

Rilonacept was generally well tolerated, and only 4 serious adverse events

were observed that were associated with underlying disease. Although not

definitive, this study does suggest some efficacy of rilonacept in selected

subtypes of systemic JIA, but a larger study with longer follow-up is

warranted.

Gattorno and colleagues[8] presented an interesting study evaluating the

pattern of IL-1beta secretion and serum levels of 27 different cytokines and

growth factors in 20 patients with systemic JIA treated with an IL-1

receptor antagonist (anakinra) 1 mg/kg subcutaneously daily. They were able

to demonstrate variable secretion of pro-IL-1beta among systemic JIA

patients, and a distinct pattern of serum cytokine levels in patients with a

complete clinical response to anakinra compared with patients with no

response to anakinra.

Costimulatory Modulators

Abatacept is a selective costimulation modulator that inhibits T-cell

activation by binding to CD80 and CD86, thereby blocking interaction with

CD28 costimulatory signal required for full T-cell activation. The efficacy

and safety results from a large randomized withdrawal study were

presented.[9,10] In this phase 3 study, all patients during the initial

4-month, open-label, lead-in period received abatacept (10 mg/kg by

intravenous infusion) on days 1 and 15 and every 28 days thereafter. At the

end of the open phase, ACR Pedi 30 responders were then randomized to

receive, in a double-blind fashion, abatacept (10 mg/kg) or placebo on that

day and at 28-day intervals thereafter for 6 months. One hundred ninety

patients entered the study; 170 completed the open phase; and 122 were

included in the double-blind phase of the study. The majority of patients

(64%) in this study had polyarthritis; 19% of the patients had systemic JIA;

and 14% had extended oligoarthritis. Thirty percent of patients had previous

biologic therapy before entering the study and 74% had concomitant

methotrexate.

Overall, ACR Pedi 30, 50, 70, and 90 response rates in the open phase were

65%, 49%, 28%, and 13%. In the double-blind phase, 53% of patients in the

placebo group flared, whereas only 20% flared in the abatacept group. During

the open phase, 6 patients reported serious adverse events, including one

case of acute lymphocytic leukemia; however, the relationship to study

medication was unlikely. No patients in the abatacept group experienced

serious adverse events during the double-blind period. The results of this

study suggested efficacy and safety of abatacept in patients with JIA, and

it demonstrated effectiveness in a subgroup of JIA patients who were

previously treated with TNF inhibitors.

In addition to the therapeutic updates, extensive updates were also

presented on practical rehabilitation issues,[11] new advances on pathways

of bone loss,[12-15] and treatment of growth failure in pediatric

inflammatory joint diseases.[16]

Conclusions

At the ACR meeting, several presentations focused on the use of new biologic

agents in patients with JIA and updated information on the efficacy and

safety of currently available biologic agents. Application of novel

laboratory technology analysis of cytokine gene expression has revealed

molecular and biological heterogeneity of patients with JIA, and may provide

the ability to distinguish patients with poor outcomes before irreversible

damage occurs. Moreover, it has been demonstrated that cytokine and genetic

profiling may identify subtypes of JIA patients who will respond to certain

therapeutic intervention, and therefore may allow for earlier initiation of

biologic agents that target specific cytokines. How these developments

translate into the clinic remains to be seen, but it is promising that

different biologic agents may be available for different subtypes of the

disease.