New Treatment Strategies in the Treatment of Juvenile Idiopathic Arthritis

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New Treatment Strategies in the Treatment of Juvenile Idiopathic Arthritis

http://romatizma.dergisi.org/text.php3?id=393

Turkish Journal of Rheumatology DOI: 10.5606/tjr.2011.012

abstract

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic

disease in childhood with an incidence of 10-19/100.000 children below the

age of 16 years, and it is also one of the major causes of acquired

disability and impairment of quality of life in childhood. Early and

aggressive control of arthritis is essential to prevent long-term

disability. Methotrexate (MTX) provides clinical benefits in JIA with an

acceptable profile of toxic effects. Nevertheless, in many cases,

inefficacy, especially in patients with polyarticular and systemic-onset

form of JIA (SOJIA) or intolerance to MTX, has led investigators to try

other therapeutic options. Biologic agents have been designed to target key

cytokines implicated in JIA including tumor necrosis factor-α (TNF-α),

Interleukin-1 (IL-1), IL-6 as well as signaling molecules involved in the

regulation of T-cell and B-cell lympocyte responses. Up to now, the U.S.

Food and Drug Administration (FDA) has approved three biologic agents for

use in moderate to severe polyarticular JIA: etanercept, adalimumab and

abatacept. In general, TNF-α inhibitors are more beneficial for children

with polyarticular disease, and the biological agents that target IL-1 and

IL-6 activity appear to be successful also in treating patients with SOJIA.

The T-cell costimulation modulator, abatacept, was shown to be effective for

the treatment of patients with moderate to severe polyarticular JIA.

Autologous stem cell transplantation has also been used in patients with

refractory JIA; however, the procedure carries the risk of treatment-related

high morbidity and mortality. The purpose of this review is to summarise the

recent advances in the treatment of JIA.

Introduction

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic

disease in childhood with an incidence of 10-19/100.000 children below the

age of 16 years, and it is also a major cause of acquired disability and

impairment of quality of life in childhood.1-5 The term JIA, like its

predecessors juvenile rheumatoid arthritis and juvenile chronic arthritis,

is an umbrella term for clinical patterns of arthritis in children.6 By

definition JIA encompasses a group of clinically heterogenous arthritides

that begin prior to age 16 years, are of unknown cause,and present with

joint pain, stiffness and swelling that persists for longer than six

weeks.1,7 According to the International League of Associations for

Rheumatology (ILAR) classification, JIA is subdivided into seven categories

which are different from each other and from adult rheumatoid arthritis

(RA).8,9 The ILAR classification is based on the number of joints affected,

the presence or absence of specific serologic findings and systemic

manifestations as outlined in table 1.

Without appropriate treatment, JIA may result in devastating consequences.

Children may experience permanent disability from joint destruction, growth

deformities or blindness. In the case of the systemic onset form of JIA

(SOJIA), untreated disease may even result in multiple organ failure and

death.7Although the outcome for children who have JIA has improved in recent

years, it is still less than ideal.10Traditionally, the overall prognosis

has been thought to be good with up to 60% of cases entering remission

before adulthood,5,10 but newer studies have not been performed to address

this issue. Various studies have shown that 25% to 70% of children with JIA

will still have ongoing, active disease 10 years after onset10,11 and ≤35%

of patients, regardless of the category of JIA, demonstrated a state of

disease inactivity of 12 months or longer while off their medication

regimen.12 These studies indicate that many patients diagnosed with JIA will

be exposed to extended periods of medication throughout their lifetimes.

Conventional therapy consists of disease-modifying antirheumatic drugs

(DMARDs), such as methotrexate (MTX), as the most common first-line DMARD

and non-steroidal anti-inflammatory drugs (NSAIDs), with the avoidance of

systemic corticosteroids. More recently, intra-articular corticosteroid

injections have been included in the treatment approach, especially in

patients with oligoarthritis. Only MTX has proven to be effective and safe

in large controlled trials.13 Nevertheless, in many cases, inefficacy,

especially in patients with polyarticular and SOJIA or intolerance to MTX,

has led investigators to try other treatment regimens. Prior to the era of

biologicals, more than 25% of polyarticular and nearly 50% of systemic

patients with JIA at five years after onset had functional limitations, and

two-thirds had radiographically evident damage.14Because none of the

available drugs has curative potential, the primary therapeutic goals are to

control symptoms, to normalize joint function and to avoid long-term joint

damage.15 The approach to treatment depends on the assessment of individual

needs and the disease subtype. Other comorbidities, such as the presence of

uveitis, may influence treatment decisions. The present article will provide

a brief update of clinical trial results and focus on recent evidence on the

safety and efficacy of biologicals in the treatment of JIA.

Prior to the development of the pediatric core set and the American College

of Rheumatology Pediatric 30 response criteria (ACR Pedi 30) in 1997, there

had been no single, uniform definition of improvement for use in clinical

trials of JIA(Table 2).16 The ACR Pedi 30 is used as the primary outcome

measure for trials of biologic agents and second line therapies. Though not

formally prospectively evaluated, the ACR Pedi 20, 50, 70, and 90 measures

are also used as outcome measures in pediatric trials. The primary goal in

the management of JIA is the achievement and maintenance of remission.

Clinical criteria defining the disease state as inactive disease (ID) or

clinical remission (CR) was developed in 2004 (Table 3).17 This definition

includes six parameters, all of which have to be satisfied for a patient to

be considered to have ID. However, they were modified recently and three

changes were made to the provisional criteria (Table 3).18

Biologic agents have been designed to target key cytokines implicated in JIA

including tumor necrosis factor-α (TNF-α), Interleukin-1 (IL-1), and IL-6 as

well as signaling molecules involved in the regulation of T-cell and B-cell

lymphocyte responses.7 In general TNF-α inhibitors are more beneficial for

children with polyarticular disease than in those with SOJIA.19 This

difference may be due to different cytokines underlying the inflammatory

response for each subtype of disease.20 Interleukin-1 and IL-6 rather than

TNF-α may be the predominant proinflammatory cytokines in SOJIA.21-23 Thus,

biological agents that target IL-1 and IL-6 activity appear to be more

successful in treating patients with SOJIA.

TNF-α INHIBITORS IN JUVENILE IDIOPATHIC ARTHRITIS

Tumor necrosis factor-α is a proinflammatory cytokine. Elevated TNF-α levels

have been identified in plasma and synovial fluid in patients with JIA24

justifying that it is a major contributor to the inflammatory synovitis and

joint damage in JIA. Tumor necrosis factor-α inhibitors are biological

agents that block the immunological effects of this inflammatory mediator.

Inhibitors of TNF-α were evaluated for efficacy in controlling JIA and have

been shown to be highly effective in the treatment of JIA patients whose

disease has been unresponsive to traditional therapies.25,26 It has become

common practice to move directly to anti-TNF therapy for the treatment of

arthritis in children who have failed to respond adequately to MTX or who

have been unable to tolerate MTX due to adverse effects.27,28 There are

three TNF-α inhibitors available for clinical use in the treatment of JIA:

Etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira).

Etanercept

Etanercept (Enbrel) is a soluble p75 TNF receptor fusion protein coupled to

the Fc (fragment crystallizable region) fragment of immunoglobulin G1 (IgG1)

that acts competitively to inhibit the binding of both TNF-α and TNF-β to

their cell surface receptors. Etanercept binds its target cytokine only when

it is in serum and lowers the quantity of free TNF-α available for the

maintenance of the inflammatory synovitis of JIA. Etanercept is administered

as a subcutaneous injection 1-2 times per week. The TNF inhibitor etanercept

is the first biological approved by the U.S. Food and Drug Administration

(FDA) for treatment of moderate to severe polyarticular JIA in children aged

two years and older. It can be used alone or as an adjunct to MTX.

Tumor necrosis factor-α inhibitors, including etanercept, appear to have a

more rapid onset of clinical effect than conventional DMARDs. In general,

clinical improvement should be seen within 4-12 weeks.27,29However, these

biologicals have not been shown to induce long-term clinical remission while

patients were off medication. In a multicenter, randomized controlled trial

(RCT), Lovell et al.30 enrolled 69 children aged 4 to 17 years with DMARD

refractory polyarticular JIA. In a three-month open label phase, all

patients received etanercept at a dose of 0.4 mg/kg twice a week and nearly

75% of patients achieved an ACR Pedi 30. Dramatic improvements were achieved

within weeks after commencement of therapy. Those patients who met the

predefined definition of response at three months were randomized to

continue etanercept or be switched to a placebo for four months. In the

double-blind part of the study, 81% of the patients who were randomized to a

placebo demonstrated disease flare compared with 28% of those who continued

on etanercept. Thus, in most children, etanercept’s effects cease within a

few weeks of its discontinuation. This study also showed that etanercept

produced significant improvement in disease activity when used in the

absence of DMARDs and appeared to be less effective in patients with SOJIA.

Etanercept has demonstrated sustained improvement in the signs and symptoms

of polyarticular-course JIA with an acceptable safety profile in an

open-label extension (OLE) of a RCT at four and eight years.31,32 At an

eight-year follow-up, an ACR Pedi 70 was achieved by 61% of patients.

A 2008 systematic review of synthetic and biologic DMARD therapy for RA in

adult patients concluded that anti-TNF monotherapy was similar in efficacy

to treatment with MTX alone. The combination of an anti-TNF agent with MTX

reduced disease activity more than did anti-TNF monotherapy or MTX alone.33

In children, nonrandomized open-label studies of the TNF inhibitors

etanercept and infliximab have shown that these biologicals safely control

active disease when used in combination with traditional therapies.34,35 In

2008, a German registry also provided information on 431 children treated

either with etanercept alone or with the combination of etanercept and MTX.

At 12 months of follow up, the number of patients with JIA reaching a ACR

Pedi 70 response was significantly higher in the etanercept and MTX group

than in the etanercept monotherapy group.36

Etanercept can induce disease remission and prevent both clinical and

radiological disease progression with significant improvements in symptoms,

function and quality of life.37,38 In another small study, bone mineral

status improved in patients who had responded to and continued etanercept

treatment for more than one year.39

Currently, little is known about when or how to stop etanercept in patients

with JIA when a good clinical response is reached. Prince et al.40 suggest

that patients with JIA should meet the criteria of clinical remission of

medication for at least 1.5 years before considering discontinuation of

etanercept and then taper off it carefully. In addition, issues such as

whether etanercept should be used before MTX (faster onset of action,

possibly more effective and less toxic) remain to be resolved. As more

biologic agents become available over the next decade, there may be dramatic

changes in our approach to the treatment of JIA.

Infliximab

Infliximab (Remicade) is a chimeric mouse-human monoclonal antibody (mAb)

that binds specifically to human TNF-α with high affinity (mAbs have a

higher affinity for a given cytokine than do soluble receptors like

etanercept) and neutralises the biological activity of TNF-α by inhibiting

its binding to its receptor.27 In JIA, MTX must be added to infliximab to

prevent the development of neutralising antibodies to infliximab that could

reduce its therapeutic efficacy. Monoclonal antibodies (infliximab and

adalimumab) bind their target not only when it is free in the serum (like

etanercept does), but also when it is bound to the cell surface. They do not

bind TNF-β. They have a higher affinity for a given cytokine than do soluble

receptors. Like etanercept, they lower the quantity of TNF-α available to

maintain an inflammatory response. Ä°nfliximab is given as an intravenous

infusion on a monthly to eight-weekly timetable. Ä°nfliximab has FDA approval

for use in adult RA, psoriasis and adult and pediatric Crohn’s disease, but

not in JIA.

In a multicenter RCT, Ruperto et al.41 enrolled 122 children aged 4 to 17

years with polyarticular JIA refractory to MTX and randomized patients to

receive infliximab (3 mg/kg/dose) or a placebo for 14 weeks. After 14 weeks,

all children received infliximab through week 44. Patients received MTX plus

infliximab 3 mg/kg through week 44, or MTX plus placebo for 14 weeks

followed by MTX plus infliximab 6 mg/kg through week 44. At 14 weeks, a

higher proportion of patients randomized to infliximab 3 mg/kg had an ACR

Pedi 30 response when compared with patients in the placebo group, but this

difference was not statistically significant. By week 52, clinical responses

meeting the ACR Pedi 50 and ACR Pedi 70 criteria were reached by 70% and 52%

of the patients respectively. There were no statistically significant

differences between the infliximab dose groups. Ruperto et al.42 also

assessed the long-term safety and efficacy of MTX plus two infliximab

dosages (3 mg/kg or 6 mg/kg) in a three year OLE. At week 204, the

proportions of patients achieving ACR-Pedi 30/50/70/90 response criteria and

inactive disease status were 44%, 40%, 33%, 24%, and 13% respectively, and

they concluded that in the limited population of JIA patients remaining in

the study through four years, infliximab was safe and effective even though

it was associated with a high patient discontinuation rate.

One small observational study compared the administration of infliximab to

etanercept in children with polyarticular JIA who had not responded to

conventional DMARDs and showed similar results (ACR Pedi 50 improvement of

80 to 90 percent) in the two groups after 12 months of treatment.34

One of the unique and distressing complications of JIA is a chronic,

non-granulamatous uveitis. Tynjälä et al.43 enrolled 45 patients to compare

the efficacy of infliximab with that of etanercept in the treatment of

chronic uveitis; 24 patients were receiving etanercept and 21 were receiving

infliximab. Patients who were taking infliximab were more likely to improve

than those taking etanercept.43 s et al.44 and Rajaraman et al.45

each reported six cases of JIA associated uveitis which were poorly

responsive to other therapies. These patients were then treated with

infliximab and had significant improvement under this therapy. Recently, the

results of a multinational survey were reported. In this study etanercept

was used in 34 patients and infliximab in 25 patients. The response to

etanercept was favourable in about 50% of the cases, moderate in about 15%,

and poor in about 35%, and for infliximab the response was favourable in

about 69% of the cases, moderate in about 31%, and poor in 0%.46 These

studies demonstrate that infliximab is more effective than etanercept in the

treatment of refractory uveitis.

Adalimumab

Adalimumab (Humira) is a recombinant fully human mAb which is administered

either weekly or, more commonly, every other week as a single subcutaneous

injection rather than by intravenous infusion. Adalimumab is associated with

a lower risk of antibody formation compared with infliximab because of its

fully humanised structure. In 2008, adalimumab was approved by the FDA as

the second TNF-α inhibitor for the treatment of moderate to severe JIA in

patients aged four years and older.

In a multicenter, randomized, medication withdrawal study, Lovell et al.47

enrolled 171 children aged 4 to 17 years with active polyarticular JIA.

Children were stratified according to MTX use and received adalimumab

subcutaneously every other week for 16 weeks. In a manner similar to the

etanercept trial, after an open-label lead-in phase of 16 weeks, patients

with ACR Pedi 30 response were randomly selected in a double blind manner to

receive adalimumab or a placebo for an additional 32 weeks. In the second

phase of the study, patients receiving adalimumab had significantly fewer

flare-ups than patients in the placebo group regardless of whether they

received MTX or not. Adalimumab demonstrated sustained improvement during

two years of treatment. After 104 weeks of OLE treatment, the proportions of

patients achieving ACR-Pedi 50/70/100 response criteria were 86%, 77%, and

40%, respectively.

Eighteen patients with uveitis were treated with adalimumab. The patients

had all failed to respond to systemic steroids, cyclosporin, MTX,

leflunomide, etanercept or infliximab. Sixteen out of 18 patients had good

responses to adalimumab.48 In another retrospective observational study by

Tynjälä et al.,49 of 20 patients with chronic uveitis treated with

adalimumab, 19 of them had been previously treated with infliximab or

etanercept. Of the 20 patients, seven showed improved activity, one showed

worsening activity, and twelve showed no change in the activity of uveitis.

The mean number of flares/year decreased from 1.9 to 1.4 during adalimumab

treatment, but this change was not significant. These studies suggest that

adalimumab is a potential treatment option in JIA associated uveitis, even

in patients not responsive to other previous anti-TNF therapies.

There is no clear evidence to support the superiority of one TNF-α inhibitor

over another and failure to respond to one agent does not preclude response

to another.50,51 In one small study, it was shown that using a third

anti-TNF agent, adalimumab, can be efficacious in patients with JIA

refractory to etanercept and/or infliximab.

Adverse effects of anti TNF-α biological agents

In order to use TNF-α inhibitors appropriately, it is important to be aware

of potential treatment-related adverse effects (AEs) of these biologicals

and the differences between them (Table 4). As well as with other DMARDs,

SOJIA is at a greater risk for AEs than non-systemic JIA categories.

The most common AEs of TNF-α inhibitors are injection site reactions to

subcutaneously administered drugs (etanercept and adalimumab) or infusion

reactions (IRs) with infliximab. The cutaneous injection site reaction

consists of local erythema and swelling which usually subsides within 24

hours. Transient injection site reactions are described in about 39% of

patients with JIA on etanercept.30 In addition to the adverse effects

reported above, there is greater immediate pain at the site of adalimumab

injections when compared to etanercept, but this is generally an

inconvenience that children find bearable.47 Infusion related reactions were

defined as any adverse event that occurred during or within one hour

following completion of an infusion. Infusion reactions are the most common

AEs in patients treated with infliximab (26-38%)41,52and the reason for

withdrawal among those receiving infliximab. These reactions are possibly

due to immune responses against the mostly humanized mouse monoclonal

antibody. In the international trial, IRs occurred in approximately 26% and

32% of patients from weeks 0-52 and 52-204 (OLE) respectively, with a higher

incidence in patients positive for antibodies to infliximab, and were more

frequent in patients treated with the lower 3 mg/kg dosage than the 6 mg/kg

dose.41,42 Serious IRs occurred in eight patients wherein five patients had

a possible anaphylactic reaction. Gerloni et al.52 enrolled 163 children (68

infliximab, 95 etanercept). In their trial, the greater number of patients

who presented AEs with infliximab (62.9%) versus those with etanercept

(54.3%) was due to IRs (sensation of thoracic constriction, dyspnea,

flushing, urticaria). Infusion reactions were the most common AEs (38.3%),

and 20.1% of patients suspended treatment because of severe IR relapse. In

this study, 12 patients receiving etanercept manifested a diffuse cutaneous

reaction that led to withdrawal in only two patients. Most centers report a

similarly increased incidence of side effects in children treated with mAbs,

especially infliximab relative to etanercept. Since adalimumab is also

administered subcutaneously, but only every other week, this mAb is at least

administered as easily as etanercept.

One of the major concerns with infliximab is the development of human

anti-chimeric antibodies (HACA) that neutralise the drug, thereby limiting

its long-term efficacy or causing IRs. In an international trial, 25% of all

patients had antibodies to infliximab with a higher incidence in the

infliximab 3 mg/kg group (38%) compared with the infliximab 6 mg/kg group

(12%).41 Infliximab seems to be more frequently responsible for newly

induced anti-nuclear antibody (ANA) and anti-double stranded DNA

(anti-dsDNA) antibody. During the OLE, newly positive ANA and anti-dsDNA

occurred in 26% and 7% of patients from weeks 52-204.42However, only rare

cases of druginduced systemic lupus erythematosus (SLE), discoid lupus

erythematosus (LE) and cutaneous vasculitis are described. In another

international trial, Lovell et al.47reported that approximately 16% of the

patients had anti-adalimumab antibodies. This percentage is greater than the

5% observed during clinical trials of adult patients with RA.53 Positive

anti-adalimumab antibody tests were less frequent among those receiving

concomitant MTX than among those receiving adalimumab monotherapy.

Serious adverse events (SAEs) are defined as events that are fatal or

life-threatening, require hospitalization or prolong an existing

hospitalization. SAEs cause a persistent or significant disability or

incapacity, a congenital anomaly, or birth defect. Etanercept offers an

acceptable safety profile in long-term treatments.31 The long-term safety

profile of etanercept was maintained for up to eight years of continuous

drug use.32 Exposure-adjusted rates of SAEs did not increase over time, and

the most common new SAEs reported beyond four years of drug exposure were

flare or worsening of disease. Between the fourth and eighth year of

follow-up, a single case of pyelonephritis was the only additional infection

reported. It is thought that the three TNF-α inhibitors will share a similar

long-term side effect.

The most important adverse effect of anti-TNF-α therapy is the increased

risk of severe infections (e.g. sepsis, pneumonia, herpes simplex and zoster

infection, pyelonephritis). After four years of an international trial of

etanercept, the overall rate of SAEs was 0.13 and of serious infections was

0.04 per patient-year.31The overall rate of SAEs (0.12 per patient-year) did

not increase with long-term exposure to etanercept. Similarly, SAEs occurred

only in 14/171 patients, seven of whom had serious infections in the

adalimumab trial.47 In the infliximab trial, however, the overall rate of

SAEs (24/117) was higher, six of whom had serious infections.41 In addition,

there may be an increased risk of opportunistic infections, particularly

fungal (e.g. histoplasmosis or coccidioidomycosis) with the use of these

agents. In patients who develop serious infections, the TNF-α blocker should

be ceased, at least until the complete resolution of the infection.27 The

reactivation of silent tuberculosis (TB), definitely related to TNF-α

inhibition, has completely disappeared as TB screening and prophylaxis are

now the rule before anti- TNF-α therapy.52 Infliximab is associated with the

greater risk.54

Over an 11-year period (1998-2009), 48 cases of malignancies in children

with a TNF inhibitor have been reported to the FDA Adverse Event Reporting

System. Half of them were lymphomas, including Hodgkin’s and non-Hodgkin’s

lymphoma; the rest included leukemia, melanoma, and solid organ cancers.

Therefore, the FDA concluded that there is an increased risk of malignancy

with TNF blockers. However, due to the relatively rare occurrence of these

cancers, the limited number of pediatric patients treated with TNF blockers,

and the possible role of other immunosuppressive therapies used

concomitantly with TNF blockers, the FDA is unable at this time to fully

characterize the strength of the association between using TNF blockers and

developing a malignancy. New-onset or relapsing central nervous system (CNS)

demyelinating disorders and neuropsychiatric AEs (depression, headache,

vertigo, fatigue, hyperactivity, nervousness, anxiety, pain amplification,

panic attacks, anorexia nervosa, optic neuropathy, hypoglossal paralysis)

have been reported, especially in patients using etanercept.52 New-onset

inflammatory bowel diseases (IBD) have also been detected in patients

treated with etanercept.52 Another concern with TNF-α blockers, especially

with etanercept, is the possible reactivation of chronic iridocyclitis

(CIC).52 TNF-α inhibitors are effective in treating JIA and have acceptable

safety profiles, but because of all these possible AEs, it is suggested that

these biologic agents be used in patients with severe disease that is

refractory to conventional therapy.

Interleukin-1 inhibitors

Interleukin-1 is a proinflammatory cytokine that triggers the production of

proinflammatory prostoglandins as well as such other proinflammatory

cytokines as IL-6 and TNF-α. Pascual et al.,23 reported that IL-1 is a major

mediator of the inflammatory cascade that underlies SOJIA. This study

demonstrated that sera from patients with SOJIA could provoke IL-1 synthesis

in tissue cultures of mononuclear cells from healthy controls, and this

cytokine represents a target for therapy in this disease. Anakinra is

currently in use in children with JIA while several other IL-1 inhibitors

(rilonacept and canakinumab) are under investigation.

Anakinra

Anakinra (Kineret) is a recombinant IL-1 receptor antagonist (IL-1 Ra) that

is approved for use in RA. Because of its short half-life, it is

administered daily by subcutaneous injection (1-2 mg/kg/day). The Anakinra

in Systemic-Onset Juvenile Idiopathic Arthritis trial (ANAJIS trial) was the

the only double-blind RCT which tested anakinra efficacy in 24 patients with

refractory SOJIA. Preliminary results reported in abstract form demonstrated

that at one month, there was a significant difference in the response rate

between patients treated with anakinra (8/12) and a placebo (1/12). Ten

patients from the placebo group switched to anakinra at month one and nine

were responders at month two. Gene expression profile analyses showed a set

of gene pathways dysregulated in SOJIA whose expression dramatically changed

upon anakinra treatment.55

The first report on the effectiveness of IL-1Ra in SOJIA was presented in

2002. In an open-label study by Reiff,56 80 patients with various forms of

JIA were treated with anakinra; patients with SOJIA had a better response to

anakinra than did those with other types of JIA (11/15 responded to

anakinra). A similar recent RCT of anakinra (1mg/kg/day; maximum 100 mg/day)

versus placebo in 50 patients with JIA by Ilowite et al.57 was unable to

demonstrate significant efficacy of the drug. Subgroup analysis, however,

showed that response rates may be higher among patients with SOJIA. Recent

case reports demonstrated that treatment with IL-1 Ra (anakinra) led to

rapid and sustained remission within a few days following the initiation of

anakinra injections in patients with SOJIA who had been resistant to

conventional DMARDs including TNF-blockade.21,58-60 An initial case series

reported by Pascual et al.23 reported a dramatic response to IL-1 blockade

among SOJIA patients with six out of nine patients treated with anakinra

achieving complete remission and two having improvement in symptoms. The

results obtained in this case series support the use of anakinra as

second-line therapy in children with SOJIA who have failed to respond to

standard therapy.

Lequerré et al.61 recently described 20 SOJIA patients treated with anakinra

and found marked and sustained improvement in less than half of the cases.

Similarly, Gattorno et al.62 described a variable response of patient’s

arthritis to anakinra in their series of 22 cases. In addition, Zeft et

al.63 reported that arthritis was less improved compared with the general

systemic symptoms of the disease. These observations indicate that although

anakinra is considered to be effective in SOJIA, there is a group of

patients who are anakinra resistant. The blockade of IL-1 signaling has a

dramatic and sustained effect in some patients with the cessation of

symptoms and a significant decrease of acute phase markers. The large group

of partial responders and non-responders are suggestive of pathological

processes that are independent of the IL-1 pathway.64,65

Injection site reactions (itch and/or erythema) and injection pain with

daily subcutaneous medication are frequent local effects of anakinra60,61,63

which may be so severe as to require the stoppage of medication. In the

study by Zeft et al.,63 over half of the patients reported localized pain or

swelling at their injection sites. Similar to TNF-α inhibitors, IL-1

blockade increases the risk of infections. Anakinra is not recommended in a

combined regimen with a TNF inhibitor because of an increased frequency of

serious adverse events, including serious infections.66 In the ANAJIS trial,

eight patients discontinued anakinra before month 12. Two patients (both on

placebos) had painful injections during the double-blind phase, one had

ileocolic symptoms leading to the diagnosis of Crohn’s disease, and one had

a case of transient hepatic cytolysis. There was also a lack of efficacy or

a disease flare in four cases.55 Varicella, localized herpes, leishmaniasis

and EBV infections have been described in children with SOJIA receiving

anakinra.61,63Three cases of macrophage activation syndrome (MAS) have also

been described.62,63 Anakinra has also been used to sufficiently treat MAS

in SOJIA patients.67,68 Without well-designed trials, the attributability of

these findings remains unclear, and the ultimate long-term safety profile of

anakinra needs to be determined.

Rilonacept

Rilonacept (IL-1 Trap/Arcalyst) is a long-acting IL-1 blocker currently

undergoing trials in children with SOJIA. Rilonacept is a recombinant fusion

protein that combines IL-1 receptor protein components with the Fc portion

of the human immunoglobulin molecule. Unlike anakinra, which requires daily

dosing, rilonacept is administered once a week.7 Preliminary results of a

double-blind, placebo-controlled study of rilonacept (2.2 to 4.4 mg/kg/week)

in SOJIA were reported by Lovell et al.[69] in abstract form. Of the 21

patients enrolled in the trial, 12 remain in the open label study and have

had good responses to rilonacept with 10 patients achieving an ACR Pedi 70

response at 42 weeks. Six out of seven patients who had failed to respond to

anakinra were found to improve on rilonacept. Adverse events were mild or

moderate in severity included generalized rash and mood alteration. SAEs

included exacerbation of pancytopenia and MAS. The OLE study on rilonacept

in SOJIA was presented at the ACR 2009 meeting. In this long-term OLE study,

sustained responses were observed in clinical and laboratory assessments in

over 50% of patients with SOJIA at two years. There was a significant

reduction in daily prednisone dosage. No deaths, malignancies, or serious

infections occurred. The authors suggested that chronic IL-1 blockade with

rilonacept was generally safe and well-tolerated.70

Canakinumab

Canakinumab (ACZ885) is a fully humanized mAb which binds specifically to

the β isoform of IL-1 (IL-1β) and neutralizes the bioactivity of human

IL-1β. It is administered as either a subcutaneous injection or an

intravenous infusion. Canakinumab shows encouraging efficacy and is well

tolerated in children with SOJIA according to a new phase II study presented

at PReS 2009, a joint congress with the 2009 Congress of the European League

Against Rheumatism (EULAR) in Copenhagen, Denmark. This open-label staggered

dose-escalation study assessed 23 children with active disease receiving a

single subcutaneous injection of canakinumab in the dose range 0.5-9 mg/kg.

Of those patients who responded to treatment (59% of initial enrollers),

100% achieved the ACR Pedi 50 score within only 15 days of receiving

canakinumab. Adverse events were predominantly mild to moderate in severity

and included infections and gastrointestinal disorders. SAEs including

worsening nausea in a patient with a medical history of gastritis and EBV

infection in another patient relating to canakinumab resolved during

treatment. Early clinical trials have established the administration of

canakinumab every two weeks to be safe and effective offering a considerable

advantage over existing treatment with anakinra which must be injected daily

and which is often poorly tolerated by patients.71

IL-6 INHIBITOR: TOCILIZUMAB

Tocilizumab (Roactemra/Actemra/MRA) is a recombinant humanized monoclonal

antibody that acts as an IL-6 receptor antagonist that has not yet been

approved by the FDA for the treatment of RA or JIA. Interleukin-6 has both

proinflammatory and anti-inflammatory effects. Plasma levels of IL-6 have

been demonstrated to correlate with disease activity in JIA patients, and

particularly elevated IL-6 levels have been noted in patients with SOJIA.24

In general, patients with SOJIA have a higher rate of treatment failure with

TNF-α inhibitors than those with other chronic arthritis subtypes indicating

that TNF-α is not the only cytokine implicated in the pathogenesis of the

disease.72 Although it is likely that the blockade of IL-1 has a dramatic

and sustained effect in some patients with SOJIA, the large group of partial

responders and non-responders suggests pathological processes independent of

the IL-1 pathway.64 Therapy with an anti-IL-6-receptor antibody

(tocilizumab) revealed much better response rates in two phase II studies in

SOJIA73,74and, more recently, in poly- and oligoarticular onset disease.75 A

randomized clinical trial is needed to define efficacy and to identify the

proper target population. This response rate is likely to be due to the fact

that IL-6 can be stimulated by IL-1 and TNF; therefore, a blockade of IL-6

will take care of processes that come mainly from the IL-1 or TNF pathways

as well other sources of stimulation of IL-6 in this disease.64

In a phase III trial by Yokota et al.,76 56 children (aged 2-29 years) with

SOJIA refractory to conventional treatment were given three doses of

tocilizumab 8 mg/kg every two weeks as intravenous infusions during a six

week open-label lead-in phase. The trial design was similar to the

etanercept trial. Patients who achieved ACR Pedi 30 response and C-reactive

protein concentration (CRP) of less than 5 mg/L were randomly assigned to

receive a placebo or continue tocilizumab treatment for 12 weeks. Patients

responding to tocilizumab and needing further treatment were enrolled in an

OLE phase for at least 48 weeks. After the end of the open label phase, ACR

Pedi 30, 50, and 70 responses were achieved by 51 (91%), 48 (86%) and 38

(68%) of patients respectively. Forty-three patients continued to the

double-blind phase. Four (17%) of the 23 patients in the placebo group

compared to 16 (80%) of the 20 patients in the tocilizumab group maintained

an ACR Pedi 30 response and a CRP concentration of less than 15 mg/L. ACR

Pedi 30, 50, 70 responses were achieved by 47 (98%), 45 (94%) and 43 (90%)

of 48 patients, respectively. SAEs occurred in 13 of 50 patients during the

OLE phase. These included anaphylactoid reactions, gastrointestinal

hemorrhages and bronchitis.

Interleukin-6 may also play a role in complications of SOJIA such as growth

impairment, systemic osteoporosis and amyloidosis.77 In this respect, in a

small group of SOJIA patients, cartilage oligomeric matrix protein (COMP)

levels were found to be lower than controls and they markedly increased

under tocilizumab therapy. These findings suggested that in SOJIA patients,

the growth cartilage turnover was suppressed during the active disease

phase, but it improved in the remission phase after tocilizumab treatment.78

T-CELL COSTIMULATION MODULATOR; ABATACEPT

Abatacept (Orencia/CTLA4-Ig) is a fully human, soluble fusion protein with a

unique mechanism of action. Abatacept consists of the extracellular domain

of the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the Fc

portion of the immunoglobulin G1 (IgG1). CTLA4-Ig binds with either CD80

(B7-1) or CD86 (B7-2) on antigen-presenting cells, thereby acting as a

competitive inhibitor of the CD28-B7 costimulatory interaction and

preventing the second activation signal received by T cells via CD28.

Abatacept thus downregulates T-cell stimulation and potentially affects many

downstream cytokines and cell types that have been implicated in the

pathogenesis of JIA.

In 2008, abatacept was approved by the FDA for treatment of patients aged

six years or older with moderate to severe polyarticular JIA. The European

Medicines Agency (EMEA) also recently (2010) approved abatacept in

combination with MTX for the treatment of moderate to severe polyarticular

JIA in pediatric patients six years of age and older as a second line

biologic after TNF inhibitors. Abatacept has been studied in a double-blind,

randomized controlled withdrawal trial including 190 children aged 6-17

years old with active polyarticular JIA refractory to at least one previous

DMARD agent including anti-TNF agents.79The design of this pivotal study was

similar to trials of the anti-TNF agents (etanercept and adalimumab) and

tocilizumab. All patients were given 10 mg/kg of abatacept intravenously in

the open-label period of four months. At the end of the open-label treatment

period, two-thirds of the 190 enrolled patients had improved by 30% or more

according to ACR Pedi response criteria. Of the patients who did respond to

abatacept, 60 were randomly assigned to receive 10 mg/kg abatacept at 28-day

intervals for six months, and 62 were randomly assigned to receive a

placebo. Flares of arthritis occurred in 33 of 62 (53%) patients receiving

placebo and 12 of 60 (20%) patients receiving abatacept (p=0.0003). During

the double-blind period, there was no difference in the frequency of AEs

between the two groups. Few SAEs were reported with no serious infections,

opportunistic infections, or serious autoimmune disorders.

Abatacept was also used in a case of refractory JIA uveitis resistant to

infliximab and rituximab, and the response was good.80 Abatacept may be a

useful alternative for treating JIA children with associated uveitis and

must, therefore, be considered as a viable treatment option.

OTHER AGENTS

Rituximab

Rituximab (MabThera/Rituxan), a selective B-cell depleting agent, is a

chimeric anti-CD20 mAb. B lymphocytes have been implicated in the

pathogenesis of rheumatoid synovitis. The precise role of B cells has not

been elucidated, but potential mechanisms include an antigen-presenting

function, secretion of proinflammatory cytokines and costimulation of T

cells. In this context, B cell depletion with rituximab has recently emerged

as a potential treatment option for patients with RA. In randomized

controlled studies, rituximab has been shown to be effective in patients

with RA81,82 and approved by the FDA for treatment of adult patients with

moderate to severe RA. There are few published case reports on the use of

rituximab in children with refractory JIA.83-85 On the other hand, in an

oral presentation at the 3rd Europaediatrics Congress 2008, eyeva et

al.86 reported on 33 patients (16 boys and 17 girls) with severe systemic

(n=24) or articular (n=9) JIA refractory to immunosuppressive therapy

including oral and parenteral glucocorticoids treated with rituximab. In

this study, 24 patients refractory to TNF-α blockers and rituximab had been

shown to produce a marked therapeutic effect including a decrease in

clinical and laboratory disease activity parameters. They suggested that

rituximab might be a promising therapeutic option in severe refractory JIA.

Thus, further RCTs are needed to clarify the role of rituximab in children

with severe refractory JIA.

Thalidomide

Thalidomide (thalomid) is a synthetic derivative of glutamic acid

(alpha-phthalimido-glutarimide) with teratogenic, immunomodulatory,

anti-inflammatory and anti-angiogenic properties. Thalidomide acts primarily

by inhibiting both the production of TNF-α in stimulated peripheral

monocytes and the activities of interleukins and interferons. This agent

also inhibits polymorphonuclear chemotaxis and monocyte phagocytosis.

Preliminary studies have demonstrated that thalidomide may be beneficial for

children with severe SOJIA.87,88 Lehman et al.87 reported the use of

thalidomide in the dose range 2 to 5 mg/kg/day administered orally in 13

children with refractory SOJIA. Ten of the 13 children had improved by 50%

or more according to ACR Pedi response criteria. In an another small study,

-Carrasco et al.88 reported three cases of recalcitrant SOJIA that had

improved dramatically after treatment with thalidomide. The most serious

toxicity associated with thalidomide is its documented human teratogenicity.

Based on present knowledge, thalidomide must not be used at any time during

pregnancy. Somnolence, dizziness, and rash are the most commonly observed

AEs associated with the use of thalidomide. Thalidomide is also associated

with peripheral neuropathy and neutropenia.

Leflunomide

Leflunomide (Arava), an orally administered inhibitor of pyrimidine

synthesis, has been shown to be a safe and effective long-term therapy for

adults with RA.89 In a multinational RCT, Silverman et al.90 enrolled 94

children aged 3 to 17 years to compare the safety and efficacy of oral

leflunomide with oral MTX in the treatment of polyarticular JIA. At week 16,

the rates of ACR Pedi 50 responses were 60% in the leflunomide group and 77%

in the MTX group (p=0.10), and the rates of ACR Pedi 70 responses were 43%

and 60% respectively (p=0.14). In both groups, the improvements achieved at

week 16 were maintained at week 48. After 48 weeks of treatment, MTX and

leflunomide both resulted in high rates of clinical improvement, and the ACR

pedi 30, 50, and 70 responses were similar between the two groups (79%, 76%,

and 70% for leflunomide, and 91%, 86%, and 83% for MTX). The incidence of

treatment-related AEs was similar in the leflunomide group and the MTX

group. The most commonly reported AEs were gastrointestinal symptoms

including liver function test abnormalities, headache, nasopharyngeal

symptoms, and reversible alopecia. Like thalidomide, leflunomide is also a

known teratogen, so women of childbearing potential must not be started on

leflunomide until pregnancy is excluded.

AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT)

Autologous stem cell transplantation has been used in patients with severe

resistant JIA. For children with severe disease who fail to achieve disease

control despite the use of multiple drugs including anti-TNF and anti- IL-6

receptor treatment, both allogenic and ASCT may offer an alternative option

for disease remission. However, the procedure still carries a high mortality

rate for an illness that does not typically have a fatal outcome. Results

from 34 children with refractory SOJIA (29 children) and polyarticular

disease who have undergone ASCT at multiple centers across Europe have been

published.91 Data demonstrated 18/34 (53%) patients had a complete response,

six showed a partial response, and seven did not respond. The incidence of

infectious complications was high and three children died. All deaths

occurred in patients with SOJIA due to MAS complicated by infection.

Autologous stem cell transplantation protocols were subsequently modified in

1999 to decrease the depletion of T-cells. After these changes, there have

been no ASCT-related deaths among 11 patients who have received the modified

regimen.92 Although this procedure has helped a number of children whose

disease was intractable, the authors point to the risk of high

treatment-related morbidity and mortality. It is hoped that with the help of

more effective anticytokine treatments such high risk procedures will not be

necessary in the future.

In conclusion, juvenile idiopathic arthritis is the most common rheumatic

childhood disease that is associated with significant morbidity including

functional disability and ocular damage. Prior to the era of biologicals,

more than 25% of polyarticular and nearly 50% of systemic patients with JIA

had functional limitations, and two-thirds had radiographically evident

damage five years after onset. New and exciting alternative medications are

emerging for children resistant to standard therapy. New data from large

RCTs have showed the efficacy of TNF-α inhibitors, the T-cell costimulation

modifier abatacept, and leflunomide for the treatment of polyarticular JIA.

Anti-IL-1 and anti-IL-6 biologicals, particularly for SOJIA patients, look

very promising as well. The mAbs to TNF-α appear to be more effective in

treating chronic uveitis associated with JIA than etanercept; however,

treatment still needs to be developed. The hope is that recent changes in

treatment approaches will result in marked improvement in long-term

functional outcomes of patients with JIA.