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Update on treatment of arthritis in children: new treatments, new goals.

Abstract

Although improved in recent years, the outcome for children who have juvenile idiopathic arthritis (JIA) is still less than ideal. Between 25% and 70% of children with JIA will still have active arthritis 10 years after disease onset, and over 40% will enter adulthood with active arthritis. Based on older publications, the fatality rate for JIA is 4-to 14-fold greater than an age- and sex-matched healthy population, and up to 39% of patients are significantly incapacitated, either wheelchair-bound or bedridden (Steinbrocker Classes III or IV). The hope is that recent changes in treatment approaches will result in marked improvement in long-term functional outcomes, although this has yet to be proven. JIA-associated chronic uveitis has a high frequency of serious complications: 20% develop cataracts, 19% glaucoma, and 16% band keratopathy. The anti-TNF biologics have all been tested in children with polyarticular JIA in blinded, placebo-controlled clinical trials, with over 70% in each trial demonstrating response that has been sustained in longer term follow-up studies. In systemic JIA approximately 50% respond to anti-TNF agents, but in many the response is not sustained. Open-label studies have shown promising results for biologic therapies that block interleukins 1 and 6 in systemic JIA.

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This article will provide a brief update of results of clinical trials and new concepts that may be applied to the management of arthritis in children. One emerging concept is a change in the classification system used for characterizing arthritis in children. The new system uses the term "juvenile idiopathic arthritis" (JIA) as the umbrella classification for chronic idiopathic arthritis in children, replacing the older term, "juvenile rheumatoid arthritis" (JRA), which has been used throughout the world for over 40 years. The new JIA classification system builds on growing data about clinical, immunologic, and genetic subtyping of chronic arthritis in children. (1) The JIA classification criteria have been formulated under the auspices of The International League Against Rheumatism. Definitions are still preliminary, but despite this a number of validation studies have been performed, and JIA is now the standard terminology in Europe and increasingly throughout the rest of the world, including North America. The Food and Drug Administration (FDA) has accepted the use of the JIA classification system in several recent clinical trials on new agents.

JIA separates chronic idiopathic arthritis in children into eight subtypes (Table 1). To fall within the umbrella category of JIA, the age of onset of arthritis must be 16 years of age or less. The duration of the objective arthritis has to be at least 6 weeks. JIA includes arthritis associated with juvenile psoriasis and inflammatory bowel disease, but arthritis associated with other chronic illnesses is excluded.

Outcome of JIA

Regardless of the terminology used, JIA or JRA, patient outcomes are still less than ideal. Publications from 1976 and 1991 suggest that the fatality rate for JIA is 4- to 14-fold greater than an age- and sex-matched healthy population. (2) Hopefully the newer treatments will decrease the mortality rate, but newer studies have not been performed to address this issue.

Various studies have demonstrated that anywhere from 25% to 70% of children with JIA will still have active arthritis as long as 10 years after disease onset. (2) Two recently published studies that provide population-based evidence of functional outcomes of JRA patients showed that 11% and 39% of the patients were significantly incapacitated, either wheelchair-bound or bedridden (Steinbrocker Classes III or IV). The outlook may not be quite as gloomy as these figures suggest, however, because the mean duration of patient follow-up in these two studies was 26 and 28 years; thus their data represent the outcome of treatment approaches that included a period of time preceding both methotrexate and biologics. (3,4) Again, it is the hope but not proven that recent changes in treatment approaches will result in marked improvement in long-term functional outcomes.

A unique and distressing manifestation of JIA is chronic uveitis. In this condition, eye damage results from the chronic inflammation of the eyes, and the chronic steroid treatment used to control the eye inflammation. A recent publication (5) described a meta-analysis of 21 published studies on uveitis in children with JIA that included a combined number of 4598 patients. The data demonstrated obvious differences in the incidence of uveitis in JIA patients based on geographic distribution. In Scandinavian studies, 18.5% of the patients demonstrated uveitis, in studies from the United States 14.5%, and studies from East Asia only 4.5%.

The frequency of uveitis varied not only by geographic area, but also by JIA subtype: 12% of children with oligoarticular JIA, 4.3% of those with polyarticular JIA, and 1.8% of those with systemic JIA developed chronic uveitis. Despite the uniform adoption of early and routine screening and treatment, the outcomes for chronic uveitis in children with JIA still include unacceptably high frequency of serious complications. In this metaanalysis, in the JIA patients with uveitis, 20% developed cataracts, 19% glaucoma, and 16% band keratopathy. The identification of effective treatments for JIA-associated uveitis that are able to prevent or minimize the eye damage is an important and unsolved problem at this time.

Efficacy Results in Recent Trials in JIA

The first anti-TNF biologic to be evaluated in children with JIA was etanercept, which was tested in children with polyarticular-course JRA. (6) This trial used a novel study design that placed all study subjects on open-label treatment with etanercept for 3 months. Those patients who met the predefined definition of response (the American College of Rheumatology [ACR] Pediatric 30) at 3 months were randomized in a double-blind fashion to continue etanercept or be switched to placebo for 4 months or until disease flare, whichever came first. The primary outcome measures for the trial were proportion in each arm that demonstrated flare and median time to flare. All study subjects in this trial were eligible to enter an open-label extension study to continue etanercept therapy. Many of these patients have now been followed for up to 5 years with ongoing therapy with etanercept. The patients in this trial had severe, longstanding, treatment-resistant polyarticular JIA with a mean of 28.5 active joints at baseline, mean physician global assessment score of 6.5 out of 10, mean parent global assessment of disease impact of 5 out of 10, mean Childhood Health Assessment Questionnaire (CHAQ) score of 1.4, and a mean C-reactive protein level of 3.4 at baseline. To be eligible for this trial, all patients had to have demonstrated either lack of adequate response or intolerance to methotrexate. In the 69 patients enrolled in this study, 74% met the definition of improvement at the end of the 3 months of open-label study and were randomized into the double-blind portion of the study. In the double-blind portion, 81% of the patients who were randomized to placebo demonstrated disease flare compared with 28% of those who continued on etanercept (P = .003). In addition, the median time to flare was >116 days in those who continued to receive etanercept (the vast majority of the patients had not demonstrated flare at the end of the double-blind portion of the study), while flare occurred at a median of 28 days in those switched to placebo (P [less than or equal to] .001). At the current time, after 5 years of open-label follow-up, over 50% of those patients remain on etanercept and continue to demonstrate significant clinical improvement in all aspects of the disease compared to their status before starting etanercept therapy. (7)

A trial of adalimumab is ongoing in children with polyarticular JIA using the same study design as the etanercept trial. The JIA patients in the adalimumab trial were stratified at enrollment to those who continued on background methotrexate during the trial and those not on background methotrexate. (8) At the end of the 4-month open-label portion of the trial, 78% of the study population satisfied the ACR Pediatric 30 level of response, 74% the ACR Pediatric 50 level of response, and 57% the ACR Pediatric 70 level of response. The ACR Pediatric 50 and 70 levels of response require that study subjects demonstrate at least 50% or 70% improvement in 3 or more of the 6 core response variables, respectively, and that no more than 1 of the 6 variables worsens by more than 30%. The proportion who demonstrated response was higher in those who used background methotrexate compared with those not on methotrexate: 88%, 85%, and 69% of the population on methotrexate versus 67%, 63%, and 45% of those without background methotrexate met the response criteria for the ACR Pediatric 30, ACR Pediatric 50, and ACR Pediatric 70 levels of response, respectively. Clinical response was demonstrated relatively quickly. More than 85% of those who would demonstrate an ACR Pediatric 30 level of response had done so after 4 weeks on therapy with adalimumab.

In a recent trial comparing 3 and 6 mg/kg body weight per infusion of infliximab to placebo in patients with polyarticular JIA, the response was likewise quite positive. (8) For the first 14 weeks of the study, patients were randomized in a double-blind fashion to receive either 3 mg/kg infliximab or placebo infusions. This parallel, double-blind, prospective study used the ACR Pediatric 30 as the primary outcome measure at study week 14. In the placebo group, 49% demonstrated an ACR Pediatric 30 level response compared with 66% in the infliximab 3 mg/kg group (P>.10). This comparison did not reach statistical significance in part because of the small sample size and in part because of the unexpectedly high placebo response rate. At the end of the 14-week phase, while maintaining the double-blind, patients on 3 mg/kg remained on that dose and those on placebo were switched to infliximab at 6 mg/kg per infusion. At the end of 52 weeks of double-blind treatment, 67% of the patients on 3 mg/kg and 80% of those on 6 mg/kg demonstrated an ACR Pediatric 30 level response. An ACR Pediatric 50 level of response was seen in 67% and 72% of patients; and an ACR Pediatric 70 response was seen in 52% and 52% of the patients on 3 and 6 mg/kg, respectively. In this trial, 33% of the subjects on 3 mg/kg did not have detectable levels of infliximab in their blood just prior to infusions given every 8 weeks (<4% of the subjects on 6 mg/kg had undetectable infliximab levels prior to the 8-week infusions). Of those in the 3-mg/kg group, 38% developed anti-infliximab antibody levels compared with only 12% in the 6 mg/kg group. In patients who demonstrated anti-infliximab antibodies, there was a 3- to 4-fold increase in the frequency of infusion reactions. These data indicate that in the treatment of children with polyarticular JIA with infliximab, if the dosing interval is every 8 weeks, as it was in this trial, then the preferred dose would be 6 mg/kg per infusion based on the lower frequency of anti-infliximab antibodies and infusion reactions at that dosage level.

An area of active investigation at this time is the proper treatment for patients with systemically active systemic JIA. Studies have shown that for systemic JIA, IL-6 and IL-1 play a much larger role in the disease manifestations than they do for polyarticular JRA. This would provide a biologic explanation for why anti-TNF therapies have been less effective in patients with systemic JIA. (9) No randomized, controlled trials of anti-TNF therapy have been performed for patients with systemic JIA, but open-label clinical experience suggests that response is seen in at best 50% of the systemic JIA patients, and many of these patients have flares of their systemic features with ongoing anti-TNF therapy. (10) However, preliminary results are very promising from a trial of a humanized recombinant anti-IL-6 receptor antibody (MRA) in 11 children with active systemic JIA (median age 9 years, median disease duration 3 years). The MRA dose was 2 mg/kg every 2 weeks for three doses and then escalated in each patient as necessary to 4 mg/kg and then if necessary to 8 mg/kg per infusion, depending on the observed clinical and laboratory effect on the disease. Clinical response was seen within a few days to 4 weeks in 10 of the 11 children. Over 90% (10/11) demonstrated an ACR Pediatric 50 level of response and 64% (7/11) an ACR Pediatric 70 response within 8 weeks of initiation of treatment with the MRA. This trial is ongoing, but the preliminary results are quite promising. (11)

IL-1 blockade with anakinra in patients with systemic JIA has also been shown to also be effective. In seven systemic JIA patients, fever resolved in 3 of the 4 patients; the mean number of joints with active arthritis decreased from 8.9 to 0.4; mean erythrocyte sedimentation rate (ESR) dropped from 70 to 14; and the mean prednisone dose could be tapered from 0.7 to 0.1 mg/kg per day at a mean of 12 months after initiation of treatment with anakinra. (12) In another study of anakinra in nine systemic JIA patients, improvement was seen in all nine with complete resolution of all clinical manifestations in 7 of 9. The fever and rash resolved in those with fever and/or rash at the time of initiation of anakinra therapy; the arthritis resolved completely in 6 of the 8 with active arthritis, and prednisone could be tapered in 6 of the 7 on prednisone. (13) This is an area of active research with other trials in development for both MRA and anti-IL-1 agents in children with systemic JIA.

Development of New Definitions of Disease States for JIA

Given the profound clinical benefits seen with the new agents in patients with JIA, validated definitions of "inactive disease" and "clinical remission" have been developed. (13) In the JIA literature over a 2-year period, over 15 different definitions for "remission" were used to characterize JRA populations. In an international, data-driven consensus-building project, a definition for "inactive disease" to be used in all JIA and JRA subtypes was developed (13) (Table 2). This definition includes six parameters, all of which have to be satisfied for a patient to be considered to have inactive disease. The patient needs to have no joint with active arthritis; no evidence of fever, rash, serositis, splenomegaly or generalized lymphadenopathy attributable to the JIA; no active uveitis; a normal sedimentation rate or C-reactive protein (or if both are tested, both must be normal); and a physician's global assessment of disease activity that indicates no disease activity (ie, the best score on the scale used). Patients who demonstrate inactive disease for 6 continuous months while on treatment satisfy the definition for "clinical remission while on medication." If they satisfy the definition for inactive disease for 12 continuous months while off all anti-arthritis medications, they then satisfy the definition for "clinical remission off medication." These definitions have been applied retrospectively to a large longitudinal database of 437 JIA patients, and 90% of the patients demonstrated at least one episode of inactive disease during a median follow-up period of 7 years. (14) The proportion of the subjects demonstrating at least one episode of inactive disease varied only slightly by JIA subtype. For rheumatoid factor-positive polyarticular JIA, rheumatoid factor-negative polyarticular JIA, systemic JIA, extended oligoarticular JIA, and persistent oligoarticular JIA subtypes, over 85% of the patients demonstrated inactive disease at least once during the follow-up period. However, the frequency of "clinical remission while on medication" and "clinical remission off of medication" varied dramatically by JIA subtype (Fig. 1). These definitions are now undergoing prospective validation by inclusion in clinical trials.

[FIGURE 1 OMITTED]

Summary

JIA is a chronic disease that is associated with increased mortality, significant morbidity including functional disability and ocular damage, and persistence of active inflammatory disease for many years in many of the patients. Methotrexate and more recently biologics have demonstrated profound improvements in both the degree and frequency of excellent disease control, most especially in patients with polyarticular JIA. New data show promise for the use of anti-IL-1 and anti-IL-6 biologics for use in systemic JIA. Treatment still needs to be developed for JIA-associated uveitis. These new treatment approaches and profound levels of improvement are requiring new outcome definitions. Definitions for "inactive disease" and "clinical remission" have been developed and retrospectively validated. These definitions should be viewed as targets for interventional trials in the future.

References

(1.) Petty RE, Southwood TR, Manners P, et al for the International League of Associations for Rheumatology. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390-2.

(2.) Levinson JE, Wallace CA. Dismantling the pyramid. J Rheumatol. 1992;19:6-10.

(3.) Zak M, Pedersen FK. Juvenile chronic arthritis into adulthood: a long-term follow-up study. Rheumatology (Oxford). 2000;39:198-204.

(4.) Packham JC, Hall MA. Long-term follow-up of 246 adults with juvenile idiopathic arthritis: functional outcome. Rheumatology (Oxford). 2002;41:1428-35.

(5.) Carvounis PE, Herman DC, Cha S, Burke JP. Incidence and outcomes of uveitis in juvenile rheumatoid arthritis, a synthesis of the literature. Graefes Arch Clin Exp Ophthalmol. 2006;244:281-90.

(6.) Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med. 2000;342:763-9.

(7.) Lovell DJ, Reiff A, Jones OY, et al. Long-term safety and efficacy of etanercept in children with polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 2006;54:1987-1994.

(8.) Lovell DJ, Ruperto N, Cuttica R, et al. Comparison of safety, efficacy and pharmacokinetics for 3 and 6 mg/kg Infliximab plus methotrexate therapy in JRA patients. Arthritis Rheum. 2005;52:S724.

(9.) Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med. 2005;201:1479-86.

(10.) Kimura Y, Pinho P, Walco G, et al. Etanercept treatment in patients with refractory systemic onset juvenile rheumatoid arthritis. J Rheumatol. 2005;32:935-42.

(11.) 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;52:818-25.

(12.) Irigoyen PI, Olson J, Hom C, et al. Treatment of systemic onset juvenile rheumatoid arthritis with anakinra. Arthritis Rheum. 2004;50:S437.

(13.) Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol. 2004;31:2290-4.

(14.) Wallace CA, Huang B, Bandeira M, Ravelli A, Giannini EH. Patterns of clinical remission in select categories of juvenile idiopathic arthritis. Arthritis Rheum. 2005;52:3554-62.

Daniel J. Lovell, M.D., M.P.H., is Levinson Professor of Pediatrics, Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Correspondence: Daniel J. Lovell, M.D., M.P.H., Professor of Pediatrics, Children's Hospital Medical Center, Location E, Room 2-129, 3333 Burnet Avenue, Cincinnati, Ohio 45229.
Table 1 Comparison of Chronic Idiopathic
Childhood Arthritis Classification Systems:
Juvenile Idiopathic Arthritis (JIA) and
Juvenile Rheumatoid Arthritis (JRA)

Idiopathic Arthritides of Childhood: Current Nomenclature *

JIA JRA

Systemic arthritis Same
Polyarthritis--RF negative Same
Polyarthritis--RF positive Same
Oligoarthritis Pauciarticular
Extended oligoarthritis Pauciarticular onset,
 polyarticular course
Enthesitis-related arthritis Not included
Psoriatic arthritis Not included
Other Not included

* RF indicates rheumatoid factor.

Table 2 Internationally Accepted Definitions for
"Inactive Disease," "Clinical Remission On
Medication," and "Clinical Remission Off
Medication" to Be Used in Children With
JIA

These three states represent durations and states of
 disease quiescence along a continuum. A patient
 has "clinical remission on medication" if s/he demonstrates
 "inactive disease" consistently for at least
 6 months while on medication for treatment of JIA.
 "Clinical remission off medication" requires demonstrating
 "inactive disease" consistently for at least 12
 months while off all arthritis medications.
Patients have "inactive disease" if they simultaneously
 meet all of the following criteria:
No joints with active arthritis (using the American College
 of Rheumatology [ACR] definition of "active
 joint")
No fever, rash, serositis, splenomegaly or generalized
 lymphadenopathy attributable to JIA
No active uveitis (as per most recent exam by an ophthalmologist)
Normal ESR or CRP (if both are tested, both must be
 normal)
Physician global assessment of disease activity indicates
 no disease activity (ie, best score on the scale used)
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Author:Lovell, Daniel J.
Publication:Bulletin of the NYU Hospital for Joint Diseases
Date:Jun 22, 2006
Words:3387
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