A CME by Dr. Lehman: Optimizing the Management of Juvenile Idiopathic Arthritis

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Optimizing the Management of Juvenile Idiopathic Arthritis

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Introduction

The key goal of pediatric rheumatologists is to maximize the ability of

children with juvenile idiopathic arthritis (JIA) to function as normal

members of society. This requires suppression of the inflammatory synovitis

and prevention of long-term damage to bones and cartilage. In addition,

optimal outcome requires minimizing the psychosocial impact of the disease

on the child and family. The clinician caring for children with JIA must

constantly weigh the balance between the severity of the inflammatory

process, the efficacy of the anti-inflammatory medications, the impact of

the illness and its therapy on the family, and the possible toxicity of the

therapeutic regimens.

The first key step in this process is recognizing that JIA is not a single

well-defined disease with a clearly defined etiology, pathogenesis, or

severity.[1] The designation of JIA includes a variety of distinct diseases

which vary greatly in their natural history, their impact on the child and

family, and in their response to medications. Many of the factors that must

be considered in attaining the optimal outcome for a young girl with a

single swollen knee (typical oligoarticular JIA) differ greatly from those

that must be considered in a teenage boy with heel pain and a swollen knee

(typical enthesitis-associated arthritis -- which is another subtype of

JIA). Similarly, the considerations for a child with the fever and rash of

systemic onset JIA are very different from those for a child with

polyarticular onset, rheumatoid factor-positive JIA.

Treatment Options

In the era before the introduction of the biologics, pediatric

rheumatologists were limited to nonspecific suppression of inflammation.

When the choices were limited to therapeutic doses of aspirin, " gold " shots

(gold sodium thiomalate or aurothioglucose), or corticosteroids, the

relative safety, efficacy, and toxicity of each agent were well known and

clearly understood. The appropriate therapeutic regimen for each child was

chosen with careful consideration of the severity of the likely outcome of

the disease process balanced against the known toxicities of the available

therapeutic choices. While there were many successes, despite our best

efforts a significant proportion of children were left with permanent

disability. The addition of methotrexate to our formulary (essentially in

place of " gold " ) increased our ability to suppress inflammation, and

dramatically increased our rate of success, but it too is a nonspecific

anti-inflammatory agent.[2]

We now have many more therapeutic choices that are far better targeted in

their suppression of inflammation. Biologics that specifically block

TNF-alpha and interleukin-1 (IL-1) are readily available, along with

additional biologics that block a variety of other cytokines in trials.

These increasingly powerful agents have led to dramatic improvements in the

outcome of children with JIA. However, our increased ability to suppress

specific aspects of the inflammatory response must be accompanied by more

accurate recognition of the efficacy with which each agent suppresses the

response and the subtypes of JIA in which specific inflammatory mediators

play an important role. Thus, before discussing optimal therapy, one must be

clear in the description of the subgroup of children with JIA being treated.

Despite the efficacy of a variety of agents in treating the chronic

synovitis that follows the acute phase of some subtypes of JIA, it is

unlikely that any biologic agent will be equally effective during the

initial active phase in all of the subgroups.

Suppression of synovitis during the initial active phase of disease is one

of the most important aspects of optimal care for children with JIA. Once

significant joint damage has occurred, little more can be done to prevent

further damage except to rehabilitate with physical and occupational

therapy, and hope the body will " repair itself. " Although the quality of

life of children with severe destructive disease has been improved by the

availability of total joint replacement, clearly preventing joint

destruction is preferable.

Early arthritis trials in adults are demonstrating improved outcome in

patients who receive an aggressive combination of medications immediately

upon presentation.[3,4] However childhood arthritis includes a wider variety

of illnesses, many of which are self-limited. This is evidenced by the

requirement that arthritis is present for at least 3 months in 1 joint or at

least 6 weeks in 2 or more joints before the criteria for a diagnosis of JIA

are fulfilled.[5] Although " early arthritis trials " are being considered for

childhood arthritis, it is uncertain whether the increased risk of toxicity

from the widespread use of corticosteroids and other agents is appropriate

for the majority of children with arthritis or will be accepted by their

parents.

Two major factors stand in the way of aggressive use of well-targeted agents

to suppress inflammation early in the course of childhood arthritis. The

biggest factor is the continuing reluctance of clinicians to advance

children to more effective therapy without an " adequate trial " of other

agents. Some believe an adequate trial requires 3 months of nonsteroidal

anti-inflammatory agents followed by a possibly longer trial of methotrexate

before a biologic agent is used. Given the greater efficacy and more rapid

onset of action of biologics with a lower incidence of hematologic or

hepatotoxic complications, this is puzzling. Although the biologics were

initially studied in patients with " methotrexate-resistant " disease, the

current package inserts for etanercept, adalimumab, and abatacept indicate

approval for the treatment of JIA without a prior requirement to " fail "

methotrexate.

There will always be parents and health care providers who are concerned

about the possible long-term side effects of medications -- in fact, all of

us are. However pediatric rheumatologists have an obligation to make parents

aware of the long-term impact of disability. Disability in childhood that

affects one's ability to participate in group activities such as recess and

physical education classes may have a far more profound effect on a child's

self esteem, emotional and psychosocial development, and long-term

accomplishments than a similar disability with its onset in adulthood.

The reluctance to initiate aggressive therapy during the early stages of

inflammatory disease stems in large part from the unfortunate inclusion of

some mild diseases under the heading of JIA. While it is clear that there

are children with mild oligoarticular arthritis and mild

enthesitis-associated arthritis (both of which are subtypes of JIA) who

improve with nonsteroidal anti-inflammatory drugs (NSAIDs) alone, children

with more severe disease do not.[1] Unfortunately, for many years parents

and clinicians who did not specialize in rheumatology were told the majority

of children " will grow out of it. " However, a growing number of studies have

demonstrated that with the exception of these mild subtypes of JIA, the

majority of children do not " grow out of it. " Instead their disease persists

and without aggressive therapy often results in chronic disability.[6]

Juvenile Idiopathic Arthritis Is Not a Single Disease

Once it is recognized that JIA does not represent a single disease entity

with a uniform prognosis, the appropriate steps to optimize the care of

children with JIA are evident. The first step is to recognize the children

who are at increased risk of chronic destructive disease. These are children

who present with systemic onset JIA, children with polyarticular JIA

(whether or not rheumatoid factor positive), and children with

oligoarticular disease who have either small joint or upper extremity

involvement.[6] Children with oligoarticular involvement of large joints who

have significantly elevated erythrocyte sedimentation rates or significant

anemia or a definite family history of psoriasis should also be considered

at increased risk.

Enthesitis-associated arthritis is considered to be a subtype of JIA, but

has a different natural history and prognosis and requires separate

consideration[7] This type of arthritis may be oligoarticular or

polyarticular in its onset. It is typically recognized in the early teenage

years when children present with significant enthesitis accompanied by

varying degrees of arthritis. It occurs in boys more often than girls. Some

children present at an earlier age, but the condition may initially mimic

oligoarticular onset disease and be impossible to differentiate in this age

group.

Pediatric clinicians must remember that arthritis is defined as any 2 of

pain, swelling, or limitation of motion. If a child has pain and stiffness,

they have arthritis even though a swollen joint is not noted. Children with

enthesitis-associated arthritis often have significant complaints of

periarticular pain without swollen joints and with a normal complete blood

cell count and erythrocyte sedimentation rate, a negative antinuclear

antibody test, and a negative test for rheumatoid factor. As a result they

are often dismissed with " growing pains " or " nonspecific complaints " and

without specific therapy. This is unfortunate as they often respond well to

NSAIDs such as nabumetone or diclofenac. I often see children who are

limited in their ability to participate in athletics by heel, hip, or low

back pain who are restored to full function simply by the appropriate choice

of NSAID.

There are several key findings that aid in the recognition of enthesitis

associated arthritis.[8] Foremost is the presence of enthesitis (tendon

insertion pain) which is most prominent around the knees, around the ankles

and at the plantar fascia insertion at the base of the calcaneus and the

distal insertion of the Achilles tendon. Second is the common presence of

lumbosacral involvement evidenced by back stiffness and loss of anterior

forward flexion in mild cases and frank sacroiliitis in more severe cases.

Clinicians caring for children with enthesitis associated arthritis must be

aware that this pattern of disease may occur in children with inflammatory

bowel disease and other systemic conditions.[7,8] These children are

typically antinuclear antibody (ANA) negative and are at less risk of

inflammatory eye disease, but should be screened for it. Any child with

continuing disease should be carefully evaluated, particularly if there is

anemia or there elevated inflammatory markers (eg, erythrocyte sedimentation

rate). In addition some of these children may ultimately develop psoriatic

arthritis or, if HLA B27 positive, ankylosing spondylitis. Initial therapy

for this subtype of JIA emphasizes the appropriate use of NSAIDs, but those

children with more severe disease may require biologic agents. The detection

of sacroiliitis either on radiographs or by magnetic resonance imaging

suggests an increased risk of progression to ankylosing spondylitis [7] It

is generally agreed that NSAIDs alone are not sufficient therapy if

sacroiliitis is present. Methotrexate and/or anti-tumor necrosis

factor-alpha (TNF-alpha) agents are often effective. The roles of other

biologics in the treatment of ankylosing spondylitis are under

investigation.[9]

In contradistinction to enthesitis-associated arthritis, typical

oligoarticular onset JIA occurs most often in young girls. Therapy for the

young child with oligoarticular onset disease who is not at increased risk

may be confined to the use of NSAIDs. However, it is important to recognize

that all NSAIDs are not equally effective in individual patients. While

ibuprofen and naproxen have few side effects and are effective for many

children, there are other children who do not respond adequately to these

drugs who do respond well to diclofenac, nabumetone, or others.

Significant inflammation with swelling and pain should not be allowed to

persist for a prolonged period even in the absence of laboratory markers of

inflammation. The major side effects of mild oligoarticular onset JIA remain

uveitis (which must be routinely screened for)[10] and leg-length

discrepancy due to overgrowth of the femur and tibia resulting from the

increased blood flow associated with chronic inflammation. Children do not

need to be given a 3-month trial of a single NSAID before changing

medications. A medication that has proven inadequately effective in a 4- to

6-week period is unlikely to prove significantly effective at 3 months and

should be replaced.

The child with a single swollen large joint who is not responding to NSAIDs

will often benefit from intra-articular steroid injection. These injections

will often result in prompt resolution of the pain and swelling and have

been shown to decrease the risk of leg-length discrepancy.[11] In some cases

intra-articular steroid injection has been used as the initial therapy.

Oligoarticular Juvenile Idiopathic Arthritis

Few children with true oligoarticular onset JIA fail to respond to NSAIDs or

intra-articular steroid injection. Any child with persistent joint swelling

after 6 months of appropriate therapy is at significant risk of long-term

disability despite the initial oligoarticular presentation and should be

treated as a child at high risk. Many rheumatology clinicians choose to use

methotrexate in this situation. However, the TNF-alpha inhibitors (eg,

etanercept and adalimumab) have greater efficacy, more rapid onset of

action,[12] and fewer significant side effects. Continued inflammation

unresponsive to NSAIDs is associated with steadily increasing joint damage.

If we are to optimize the care of these children and minimize long-term

disability, prompt institution of effective therapy is always essential.

For children with oligoarticular onset disease with " high risk " factors at

presentation and children with polyarticular onset disease a brief trial of

NSAIDs is often appropriate. This is because there are many forms of

transient arthritis that initially mimic JIA, but resolve spontaneously over

a period of weeks. It is essential to recognize when the NSAIDs are proving

ineffective or inadequate. Although a longer trial of NSAIDs may be

considered, it is appropriate to initiate therapy with a disease modifying

agent (eg, an anti-TNF-alpha agent) in children with significant risk

factors who have not responded to a 6- to 8-week trial of NSAIDs. Further

delay in initiating disease-modifying therapy risks progressive joint

damage.

The majority of children with significant JIA are rapidly responsive to

anti-TNF-alpha agents such as etanercept, adalimumab, and infliximab. For

those with continued active disease despite a 6- to 8- week trial of an

anti-TNF-alpha agent, the addition of methotrexate may prove beneficial. The

combination of an anti-TNFα agent and methotrexate is synergistic and this

regimen has been beneficial for the majority of children (adult

studies).[13] This combination is effective for the majority of children

with rheumatoid factor positive, anti-CCP positive polyarthritis and many

children with systemic onset disease. However, the majority of children who

fail to respond to this regimen belong to these 2 JIA subgroups.

Children with polyarticular-onset rheumatoid factor-positive, anti-CCP

positive arthritis who fail to respond adequately to anti-TNF-alpha agents

and methotrexate may be treated with abatacept or rituximab. Abatacept has

been specifically approved for use in JIA. It was clearly shown to be

effective for the treatment of JIA in a placebo-controlled withdrawal trial,

but it is less efficacious in children who have previously failed

anti-TNF-alpha agents than in others.[14] Rituximab is not currently US Food

and Drug Administration (FDA) approved for use in JIA and there are no

published trials in the pediatric age group. Rituximab has been demonstrated

to be effective in adults with rheumatoid arthritis.[15] Both agents have

been beneficial for children with severe disease in my experience.

Systemic Onset Juvenile Idiopathic Arthritis

Children with systemic-onset JIA represent a special case. During the acute

phase of the disease, which is complicated by the presence of fever and

rash, corticosteroids are often necessary to control their symptoms. Every

effort should be made to minimize the dosage of corticosteroids because of

the associated side effects. Methotrexate has been more consistently

efficacious than anti-TNF-alpha agents for this disease. IL-1 and IL-6 have

been shown to play a significant role in the systemic manifestations and

anakinra and tocilizumab (not yet licensed in the United States) have both

shown efficacy.[16-18] Rilonacept is an IL-1 trap molecule recently licensed

for the treatment of cryopyrin-associated diseases and may prove efficacious

for severe systemic-onset JIA. Cyclosporine is often effective in those

children with early manifestations of macrophage activation syndrome, but

corticosteroids are often required for adequate control.[19] Abatacept has

been utilized to control arthritis following the systemic phase of JIA, but

children with active systemic disease were excluded from the studies

reported.[14] Minimizing the psychosocial impact of the disease on the child

and family is one of the key concepts of optimal care I mentioned at the

beginning of this article. It is important to learn the optimal therapy for

a child with JIA. However, it is equally important to learn how to present

that information to families in a way that minimizes the psychosocial impact

and maximizes the family's acceptance -- a skill that is rarely, if ever,

taught during one's training.

Parents and other family members have been conditioned by our society to

recognize the occurrence and severity of childhood cancer. When confronted

with a diagnosis of cancer, most families are immediately resigned to the

need to accept aggressive therapy. By contrast, most families remain shocked

that children " get arthritis, " and are unprepared to accept the far less

likely side effects of appropriate anti-inflammatory therapy. While the

clinician caring for a child with arthritis may recognize on the initial

visit that a child is at risk of joint destruction and requires aggressive

therapy, the child's parents most often do not. It may be appropriate to

begin by simply providing an NSAID and giving the family a chance to accept

the diagnosis of arthritis, but this carries the risk that the family will

again be unprepared if/when a biologic medication is subsequently

recommended. In general, families are unfamiliar with biologics, afraid of

" shots, " and wary of newer medications.

What Can be Done to Optimize Outcomes?

It is important to do 2 things to counter these problems to obtain optimal

compliance and attain the optimal income. The first is to appropriately

explain the nature of the disease to the family and (where appropriate)

dispel the widespread myth that " most children grow out of it. " This should

be accompanied by an appropriate explanation of the expected risks and

benefits of aggressive therapy and the damage that results from uncontrolled

inflammation. Families often come to me for a second opinion because they

went to a follow-up visit with their initial specialist thinking the child

was " okay, " only to be shocked by a recommendation to immediately start more

aggressive therapy. The package inserts for methotrexate and the biologics

carry a variety of frightening warnings that many parents are unwilling to

accept without appropriate introduction. I often deal with this by providing

the family with information on more aggressive therapy at the time of the

first visit where I worry that it might become necessary. This gives the

family a chance to read and consider the materials and evaluate the child's

condition before the decision has been made to prescribe the medication. It

also provides an opportunity to discuss the child's progress and condition

and (if possible) allay the parents' concerns at the next visit. Prepared

rather than surprised, most families are willing to accept the importance of

aggressive therapy.

Conclusions

The key to effective therapy for all of these subtypes of JIA is suppression

of inflammation and prevention of joint damage -- the earlier in the disease

course that appropriate steps to suppress inflammation are initiated, the

less the damage. " Early arthritis " studies in adults suggest that aggressive

therapy with a combination of agents shortly after presentation leads to a

superior long-term outcome.[3,4] Because of the increased risks of

corticosteroid usage (eg, growth retardation) in the pediatric age group the

applicability of these studies to children with JIA is not yet clear.

However, that does not negate the importance of early aggressive

intervention. Clinicians caring for children with JIA must be clearly aware

that there are a variety of NSAIDs available for children with low risk

disease that vary in efficacy. In addition, once a child is recognized to

have ongoing destructive disease, there should be no delay in the initiation

of aggressive disease-modifying therapy. In the past this most often meant

the addition of methotrexate. However, the currently used biologic agents

carry little if any increased risk of toxicity and have a faster onset of

action with a lower incidence of bone marrow suppression or hepatotoxicity.

Only by being aware of the diverse conditions included within the

classification of JIA can clinicians caring for children with JIA be

prepared to recognize when a child is likely to do well without aggressive

therapy and when aggressive therapy will most likely be required. It is

important to make this distinction quickly to appropriately prepare the

family. Once the children at risk have been recognized, every effort should

be made to prevent progression of inflammation and the resultant joint

damage and disability. This has been greatly simplified by the development

of a variety of biologic agents with a rapid onset of action and relatively

minor short-term toxicities.

The subtypes of JIA are not identical in their etiology or pathogenesis.

While a variety of agents are effective because they nonspecifically

suppress inflammation, others are effective because they suppress cytokines

that are involved in the majority of inflammatory processes. We are

beginning to understand that different cytokines play varied roles in

different subtypes of JIA. At present, systemic-onset JIA is the most

striking example, but it is likely other examples will become apparent in

the future. With better characterized disease and better characterized

therapies, health care providers caring for these children can look forward

to steady improvement in disease control and reduced medication toxicity in

the future.

To attain our goal of optimal outcome, families caring for children with JIA

must be appropriately educated about the importance of disease control and

take steps to minimize the family's concerns about safety, efficacy, and

importance of these medications. The most effective therapy imaginable will

prove ineffective if the clinician does not recognize the diagnosis and the

need to prescribe the medication or lacks the knowledge and understanding

required to convince the family to administer it.

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Authors and Disclosures

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Author: J.A. Lehman, MD

Professor of Clinical Pediatrics, Weill Medical College of Cornell

University, New York, NY; Chief, Division of Pediatric Rheumatology,

Hospital for Special Surgery, New York, NY

Disclosure: J.A. Lehman, MD, has disclosed that he has received

grants for clinical research from Celgene. Dr. Lehman has also disclosed

that he has served as an advisor or consultant to Genzyme, Genentech, Roche,

and UCB, and has served on the speaker's bureau for Abbott, Amgen, and

Wyeth.

Editor: Helen Fosam, PhD

Editorial Director, Medscape Rheumatology

Disclosure: Helen Fosam, PhD, has disclosed no relevant financial

relationships.

Jayashree Gokhale, PhD

Scientific Director, Medscape, LLC

Disclosure: Jayashree Gokhale, PhD, has disclosed no relevant financial

relationships.

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