have been associated with a greater than twofold increased risk of cardiovascular

events (MI, stroke, and heart failure), as well as the risk of developing hypertension

with long-term use (at least 6–12 months).

193,194 Therefore, the lowest effective

corticosteroid dose is preferred for the shortest duration of time possible.

28 The onset

of action of corticosteroids is relatively rapid, and their immediate benefits will

allow W.M. to maintain his current employment and continue taking care of

responsibilities at home. The corticosteroid dose can be decreased gradually and

eventually discontinued as W.M. begins to respond to HCQ therapy. An important

goal of low-dose corticosteroid treatment is to provide bridge therapy until the

DMARD therapy becomes effective, in hopes of then being able to taper and

discontinue the corticosteroid.

CASE 44-10, QUESTION 2: Would intra-articular corticosteroid injections be a safe and effective treatment

option for W.M.?

Intra-Articular Corticosteroids

Intra-articular corticosteroid injections are safe and effective for pain relief in

patients with RA. This strategy is most sensible when flaring occurs in one or a few

joints.

195 Systemic side effects are minimal when compared with oral corticosteroid

therapy. Although onset of action is virtually immediate, effects are often short-lived.

W.M. could benefit from the use of intermittent intra-articular corticosteroid

injections for the treatment of RA flares.

JUVENILE IDIOPATHIC ARTHRITIS

Juvenile idiopathic arthritis is a heterogenous group of chronic arthritic conditions of

unknown etiology, occurring before 16 years of age. It is the most common chronic

rheumatic disorder in childhood, afflicting approximately 300,000 children in the

United States, affecting all races equally with peak age of onset between two and

four. However, new cases are seen throughout childhood and often continue into

adulthood, causing significant morbidity and physical disability.

196–198

Clinical Presentation and Classification

By definition, symptoms of JIA (joint inflammation involving swelling, pain, limited

ROM, warmth, and erythema) present before the age of 16 and must last for at least 6

weeks in at least one joint.

199 Similar to other rheumatologic disease classifications,

the diagnosis of JIA is a diagnosis of exclusion; infectious, traumatic, and other

etiologies must be ruled out first.

200

As with adult RA, JIA begins with synovial inflammation. Because children often

cannot articulate complaints, morning stiffness and joint pain may manifest as

increased irritability, guarding of involved joints, or refusal to walk. Fatigue and

low-grade fever, anorexia, weight loss, and failure to grow are other symptoms.

Patients with JIA are categorized as having one of the following seven types of

disease as established by the International League of Associations for Rheumatology

(ILAR): (1) systemic, (2) oligoarthritis, (3) polyarthritis RF+, (4) polyarthritis RF−,

(5) psoriatic, (6) enthesitis-related, and (7) undifferentiated (patients who do not

fulfill criteria of other JIA subsets).

201 For a catalog of JIA images, including

radiography and ophthalmologic photographs, please go to

http://images.rheumatology.org/search.php?

searchField=ALL&searchstring=JIA.

The most common type of JIA is oligoarthritis, which comprises about 50% to

60% of all JIA cases. This type of JIA typically presents before the age of 6 years,

with 80% cases afflicting girls. Oligoarthritis patients present with four or fewer

affected joints, most commonly in the ankles. Those who do not progress beyond four

joints are categorized with persistent oligoarthritis, but 50% may eventually develop

arthritis in additional joints requiring a change in disease classification to extended

oligoarthritis.

198,201

JIA is classified as a polyarthritis when the disease involves five or more joints

during the first 6 months of the disease with few or no systemic manifestations of

disease.

201 Polyarthritis may be RF+ or RF− and accounts for up to 40% of all JIA

disease, the majority of which is RF−.

202 Both types affect girls more often than boys.

Disease onset is typically seen at age 8 or older, and most often in adolescents. RF+

polyarthritis presents very similarly to adult-onset RA, involving aggressive,

erosive, and symmetric joint inflammation which may lead to general growth

retardation, as well as fatigue, morning stiffness, and elevated inflammatory

markers.

196,198

Psoriatic JIA accounts for a small number of all JIA cases (about 5%) and is

diagnosed if chronic arthritis and psoriasis are both evident. Children may also be

diagnosed with psoriatic JIA if any two of the following are present: dactylitis

(finger or toe inflammation), onycholysis or nail pitting, or family history of

psoriasis.

196,201

Enthesitis-related JIA is manifested as inflammation of the enthesis (the site of

attachment of tendon to bone) along with arthritis, typically in the lower limbs, in

boys older than 6 years old. Children with enthesitis-related JIA have at least two of

the following in addition to arthritis or enthesitis: inflammatory lumbosacral or

sacroiliac joint pain, HLA-B27 positivity, symptomatic anterior uveitis, or a family

history of enthesitis-related JIA or ankylosing spondylitis (first-degree relative).

201,203

CASE 44-11

QUESTION 1: J.R., a 4-year-old girl, is brought to the hospital for high fever and arthritis. Several weeks

before admission, J.R. had a daily fever ranging from 103°F to 106°F. One week before admission, her knees

became painful and swollen. J.R. is listless and irritable during her physical examination, and her rectal

temperature measures 102.4°F. She refuses to walk. The right hip is tender, and the right wrist and both knees

are warm, red, and swollen. Minimal generalized lymphadenopathy and splenomegaly are present. The

Westergren ESR is 82 mm/hour, the white blood cell count is 37,000 cells/μL with a mild left shift, and

hematocrit is 33%. Cultures of the throat, urine, stool, and blood are negative. MD global assessment is 4. An

intermediate-strength purified-protein derivative, antistreptolysin-O titer, ANA titer, and RF titer are normal, as

are radiographs of the chest and involved joints. An electrocardiogram reveals only tachycardia. After

withholding aspirin, an evanescent rash becomes apparent in conjunction with fever spikes. What signs and

symptoms

symptoms of JIA does J.R. manifest?

The last category of JIA is systemic JIA, which is distinguished from other forms

of the disease by the presence of hallmark systemic features including rash,

lymphadenopathy, hepatomegaly or splenomegaly, serositis and cyclical high-spiking

fever. J.R. exhibits these distinguishing symptoms and, in addition she also

experiences joint pain in her knees, with other commonly afflicted joints including

the wrists and ankles. The pain often worsens when fever is elevated, but may not be

clinically evident at disease onset. Systemic JIA occurs equally in girls and boys and

comprises approximately 15% of all JIA cases. Children presenting with this subtype

of JIA may also have a normocytic, hypochromic anemia, elevated ESR, and

thrombocytosis. Leukocytosis is common, and a white blood cell count of 30,000 to

50,000 cells/μL is seen occasionally. A positive RF titer is uncommon in JIA and is

present in only 5% to 10% of all cases.

197,198

p. 900

p. 901

Prognosis

CASE 44-11, QUESTION 2: What is the expected prognosis for J.R.?

Features of poor prognosis for patients with JIA generally include arthritides that

involve cervical spine or hip joints, involvement of the ankle or wrist coupled with

significant or prolonged elevation of ESR or other inflammatory markers, and

radiographic damage.

199 Disease remission is qualified by lack of active arthritis in

joints, absence of systemic symptoms (rash, fever, lymphadenopathy, etc.),

symptomatic uveitis not present, normal ESR or CRP, and no disease activity

measured on a physician’s global assessment scale. While only 5% of patients

achieve true remission, sustained periods of good control is becoming more common

with treatment advances, and up to 35% to 50% of patients achieve clinical

remission on medication therapy. Despite improvements in care, complete remission

is still uncommon, and up to one-third of patients with JIA do experience long-term

disability and decreased quality of life. Preservation of joint function is least

promising in children with RF+ polyarthritis.

204–206 Although J.R. is exhibiting some

poor prognostic indicators (hip and wrist involvement, elevated ESR), it is unclear

whether these are long-term manifestations. Normal ANA and RF titers and the

absence of radiographic damage are favorable for J.R.

Treatment

The goals of JIA treatment are to minimize joint inflammation and its destructive

effects, control pain, preserve or restore ROM, facilitate an acceptable quality of

life, and achieve long-term disease remission. Choice of medication therapy requires

consideration of type of JIA, current treatment, degree of disease progression, level

of disease activity, and prognosis.

199

NONPHARMACOLOGIC THERAPY

In addition to treatment with medication, many patients with JIA can benefit from

nonpharmacologic efforts to help preserve joint flexibility, maintain ROM, and

prevent disability in adulthood. Patients with JIA are often less physically active and

more easily fatigued than their disease-free peers, and they may meet developmental

milestones later than children of the same age.

207 Children with JIA are also more

prone to decreased bone mineral density than their peers.

CASE 44-11, QUESTION 3: J.R.’s parents understand the need for medication therapy but also want to

encourage lifestyle interventions as a way to promote health and combat disease complications. What

recommendation can the physician give to J.R. and her family once her acute symptoms are stabilized?

Heat and cold therapy, massage, and regular physical activity can all help reach

disease treatment goals of minimizing joint inflammation, controlling pain, and

improving quality of life. Regular physical activities, including muscle-strengthening,

ROM activities, stretching, and endurance training, are safe and do not worsen

arthritis. Weight-bearing exercise can help prevent bone loss, but it should be

avoided when joints are acutely inflamed. At these times, low-impact sports such as

swimming or bicycling can be enjoyed. Physical therapy and occupational therapy

can also help pediatric patients hone gross and fine motor skills, balance, and

coordination.

207,208 Once J.R.’s status improves, she should be encouraged to

participate in regular exercise and organized therapy sessions to improve exercise

capacity and preserve joint functioning.

PHARMACOLOGIC THERAPY AND TREATMENT CONSIDERATIONS

While ILAR differentiates JIA into seven disease types, the ACR treatment

recommendations classify treatment groups by a different system, since there is little

evidence to support pharmacologic decisions based on disease categorization itself.

The five treatment groups consist of (1) history of arthritis in four or fewer joints, (2)

history of arthritis in five or more joints, (3) active sacroiliac arthritis, (4) systemic

arthritis without active arthritis, and (5) systemic arthritis without active arthritis.

199

However, the 2013 ACR update on systemic arthritis subdivides this treatment

category into three distinct clinical phenotypes: (1) with active systemic features and

varying degrees of synovitis, (2) without active systemic features and with varying

degrees of active synovitis, and (3) features concerning for macrophage activation

syndrome (MAS).

The history of arthritis of four or fewer joints treatment group includes ILAR

disease-classified patients with extended oligoarthritis, RF− polyarthritis, RF+

polyarthritis, psoriatic arthritis, enthesitis-related arthritis, and undifferentiated

arthritis, all have had no more than four affected joints in their disease course.

NSAIDs as monotherapy may be initially considered for those with low disease

activity; however, step-up therapy includes intra-articular glucocorticoid injections

followed by methotrexate, and finally TNF-α inhibitors in those with poor response.

NSAIDs can always be used as adjunctive therapy for any patient with JIA; however,

it should never exceed 2 months as monotherapy without addition of other treatment.

Triamcinolone hexacetonide is the intra-articular glucocorticoid of choice and can

provide clinical improvement for a minimum of 4 months; step-up to csDMARD

therapy may be warranted if symptoms are not controlled within this period.

209,210

MTX may be initiated in those who either fail initial therapy with NSAIDs and intraarticular injections or in those who have high disease activity and poor prognosis. In

those with enthesitis-related JIA specifically, SSZ is the initial csDMARD over

MTX because of evidence of improved clinical symptoms and long-term outcomes.

203

Finally, in those who still lack response after 3 to 6 months of optimized MTX

therapy, TNF-α inhibitors may be initiated. Since publication of the ACR treatment

recommendations, tocilizumab has been approved for polyarticular JIA. While place

in therapy is not specified except for systemic JIA, it may be alone or in combination

with methotrexate as step-up from initial therapy.

57

Patients who experience arthritis of five or more joints in the duration of disease

course should have MTX considered as first-line therapy. The role of NSAIDs is deemphasized in this treatment group; patients may undergo a short 1- to 2-month

course, but quick escalation to DMARD therapy is cornerstone in order to slow

disease progression. Because of extensive experience with LEF, this agent may be

considered as an alternative to MTX or in those with high disease activity and poor

prognosis. For those who fail DMARD therapy after 3 to 6 months, a TNF-α inhibitor

may be initiated, followed by switch to another TNF-α inhibitor or abatacept if

response remains poor after 4 months of initial bDMARD therapy. For those who fail

both TNF-α inhibitor and abatacept, rituximab is the last-line bDMARD agent.

Patients with active sacroiliac arthritis may include individuals from any of the

JIA disease categories, but the treatment group must be defined by both clinical and

imaging evidence of the disease. Step-up therapy quickly intensifies to TNF-α

inhibitors following failed trials of optimized NSAID or csDMARD (MTX or

SSZ).

199

Systemic JIA is subdivided into three treatment categories based on clinical

phenotype. In those without active systemic features, NSAIDs can be used as

monotherapy initially but should be reserved for those with low disease activity and

should not be continued as sole therapy for longer than 2 months. If four or fewer

joints are involved, injectable glucocorticoids may be considered

p. 901

p. 902

concurrently, but if five or more joints are impacted, favor should be placed on

either MTX or LEF over injectable glucocorticoid. Following treatment failure of

csDMARD, several bDMARDs including abatacept, anakinra, and tocilizumab may

be considered.

About 10% of pediatric patients with JIA develop MAS, a life-threatening

complication characterized by fever, pancytopenia, liver insufficiency, and

coagulopathy among others and if hospitalized, it is associated with a 6% mortality

rate. In these patients, anakinra, calcineurin inhibitors, and systemic glucocorticoid

therapy should be considered.

197

CASE 44-11, QUESTION 4: Are NSAIDS an appropriate choice for initial drug therapy for the treatment of

systemic JIA in patient J.R.?

NSAID therapy may be considered as first-line treatment for 1 to 2 months in most

cases of oligoarticular and polyarticular JIA.

199 However, the use of NSAIDs as

monotherapy beyond 2 months in patients with active arthritis is not recommended,

regardless of the presence of poor prognostics features.

199

In the case of systemic

JIA, as with patient J.R., NSAIDs may be considered as monotherapy in patients with

JIA with an MD global <5 and any level of joint involvement. However, therapy

should be stepped up in patients with continued disease activity after 1 month on

NSAID monotherapy.

197 NSAIDs are useful in systemic JIA as they target joint

inflammation as well as the febrile episodes common in systemic JIA.

198,211 These

medications work to control pain, fever, and inflammation by inhibiting prostaglandin

synthesis and are usually fairly well tolerated by children. Analgesic effects usually

occur first, and with continued use NSAIDs’ anti-inflammatory effects will begin

within a few weeks.

Many of the traditional NSAIDS as well as celecoxib have been used to treat JIA.

The most commonly prescribed NSAIDs for JIA are naproxen and ibuprofen.

Naproxen is approved for the treatment of JIA in patients ≥2 years old at a dose of 5

mg/kg by mouth twice daily and is advantageous in school-age children because of

the convenient dosing interval and availability in liquid or tablet formulations.

211

Ibuprofen is indicated for the treatment of JIA in patients aged ≥1 years old. For

patients from 1 to 12 years, ibuprofen is recommended at a dose of 30 to 40

mg/kg/day given in three or four divided doses. Ibuprofen is also available in tablet

and liquid formulations.

212

In most cases, at least two different NSAIDs should be tried before ruling out this

group of medications owing to lack of efficacy or tolerability.

213 Failure to respond

to an NSAID in a particular chemical class does not rule out the efficacy of others in

the same class. As with adults, it is not possible to predict a pediatric patient’s

response to any one NSAID.

Given the presence of active systemic features (fever, lymphadenopathy,

splenomegaly, and evanescent rash) along with an MD global of <5 and AJC of 4

(right hip, left and right knees, right wrist), either an NSAID or anakinra would be the

appropriate first-line agents for J.R.

197 Either ibuprofen or naproxen would be

sensible first choices. Ibuprofen is available over-the-counter in liquid and chewable

forms, which is an important consideration for a 4-year-old. Naproxen is also

available in an oral liquid suspension by prescription and can also be considered as

initial therapy.

CORTICOSTEROIDS

CASE 44-11, QUESTION 5: J.R., who weighs 33 lb, was prescribed Naproxen 125 mg/5mL oral suspension

at a dose of 75 mg BID. Her parents have given her the medication twice daily as directed for the past 4

weeks, but she continues to have disease activity with persistent fever. What should the next step in therapy be

for J.R.?

It is inappropriate to continue NSAID monotherapy in a patient who continues to

have disease activity after 1 month of treatment. Therefore, alternate treatment

options should be explored. The ACR guidelines recommend the use of systemic

glucocorticoid therapy in patients with systemic JIA, but not in patients with

nonsystemic JIA.

199

Despite the potential for serious adverse effects associated with high-dose or

long-term therapy, the use of low-dose corticosteroids is sometimes necessary to

control disease flares or provide therapeutic relief during initiation of DMARDs

with slow onsets of action. Systemic glucocorticoids may be considered as

adjunctive therapy for systemic JIA at any point in treatment.

197

It is preferable that patients take the lowest effective corticosteroid dose for the

shortest duration possible to avoid long-term side effects such as hypertension and

osteoporosis. Oral corticosteroids are typically dosed once daily in the morning to

best mimic physiologic cortisol release and minimize suppression of the

hypothalamic–pituitary–adrenal axis. For J.R., systemic glucocorticoids are an

appropriate next step in therapy and may be considered as adjunctive therapy, if

necessary, throughout the course of her disease.

CASE 44-11, QUESTION 6: What corticosteroid side effects should J.R. be counseled about?

Common side effects of steroids include GI upset and damage to the GI mucosa,

mood changes including depression or hyperactivity, and increases in blood pressure

and blood sugar.

212 Corticosteroids may also cause impaired skin healing,

osteoporosis (especially with long-term use), and vision problems such as cataracts

and glaucoma. J.R.’s parents should be counseled about receiving vaccinations

during corticosteroid therapy because immunosuppression may attenuate an

appropriate immune response. Inactivated vaccines are safe for use in

immunocompromised patients and should be administered if indicated.

212

Immunocompromised patients typically have a weaker immune response to vaccines

when compared with healthy patients; therefore, higher doses or more frequent

revaccinations may be necessary.

Greater caution must be taken with live-virus vaccines in immunosuppressed

patients. The risk of immunosuppression in patients receiving corticosteroids is

dependent on corticosteroid dose, duration, and route of administration; local

corticosteroid treatments (e.g., topical, inhalation, and intra-articular) do not put

patients at risk.

214 Patients receiving short-term corticosteroid therapy (i.e., <2

weeks), every-other-day dosing with a short-acting corticosteroid, or doses of no

more than moderate range can usually receive live-virus vaccines. Corticosteroid

dosing that is considered high risk for immunosuppression is the equivalent of at least

prednisone 2 mg/kg/day or 20 mg/day; patients receiving corticosteroid dose

equivalents in this range should not receive live-virus vaccines. Patients receiving

high-dose corticosteroids systemically for 2 or more weeks should wait at least 3

months before receiving a live-virus vaccine.

214

Intra-Articular Corticosteroid Therapy

CASE 44-11, QUESTION 7: J.R.’s pain in both knees has continued to limit to her willingness to walk. Her

parents are concerned about her lack of activity and would like to know if there are any options for relieving her

pain more quickly. Would intrarticular glucocorticoid therapy be an appropriate option for reducing knee pain in

J.R.?

Intra-articular corticosteroid therapy seems to be highly effective in JIA. Injections

are typically reserved for patients who have not responded to conventional NSAID

therapy or who present with monoarthritis or oligoarthritis, and current guidelines

p. 902

p. 903

suggest they are recommended for all patients with JIA having active disease in

four or fewer joints, regardless of activity level, prognosis, or joint deformity.

199

Intra-articular steroid injections are also recommended as adjunct therapy in other

forms of JIA, including patients with active disease in five or more joints and those

with systemic JIA. Compared with NSAIDs, steroid injections are much better able

to reduce duration of joint pain.

213 Full disease remission of injected joints lasting

longer than 6 months can be expected in more than 80% of patients with JIA, and

60% of patients may be able to discontinue all oral medications with lasting disease

remission in treated joints.

215

In one study, after an average of 30 months of followup, long-term negative effects of corticosteroid therapy (e.g., joint stability,

osteonecrosis, and soft tissue atrophy) were not encountered. As a result, intraarticular corticosteroid therapy seems to be a safe and effective option for JIA,

particularly in oligoarticular disease limited to a few joints.

198

Intra-articular steroid injections would be appropriate adjunctive treatment for

J.R. Her parents should be advised to limit her activity for a couple of days after the

injection, but she should be encouraged to resume normal activity and physical

therapy to maintain joint flexibility and ROM soon after the treatment.

213 Repeated

intra-articular injections are usually given several months apart. Side effects include

local lipoatrophy or articular calcification, both of which do not present many issues

clinically.

DISEASE-MODIFYING ANTIRHEUMATIC DRUGS

CASE 44-11, QUESTION 8: After 2 weeks of glucocorticoid monotherapy, J.R. continues to have moderate

disease activity. Her doctor would like to start DMARD therapy, but it is uncertain whether a csDMARD or

bDMARD would be preferred. What would you recommend?

Early csDMARD therapy should be considered for patients with history of arthritis

of four or fewer joints (e.g., persistent oligoarthritis) as well as patients with history

of arthritis of five or more joints (e.g., extended oligoarthritis and polyarthritis [RF

positive and RF negative]).

199 MTX is the DMARD of choice for these forms of JIA.

For systemic JIA, MTX or leflunomide should be considered first-line in patients

without systemic features and AJC > 4 and as second-line therapy and beyond for any

number of active joints. MTX or leflunomide may also be considered for systemic

JIA as second-line therapy and beyond for patients with systemic features. However,

csDMARDs have not been shown to be as effective against systemic JIA as

compared to other forms of JIA.

216,217 For a patient like J.R. with systemic JIA with

active systemic features, MTX or lefluonomide could be considered, but given

relative lack of efficacy, other options, including several of the bDMARDs, are

preferred.

Biologic Agents

CASE 44-11, QUESTION 9: Given that csDMARDs would not be an optimal treatment option for J.R.,

which of the bDMARDs would be most appropriate for treating systemic JIA in J.R.?

There are currently four FDA-approved biologic agents available to treat forms of

JIA: etanercept, adalimumab, and abatacept for JIA and canakinumab for systemic

JIA. There are also several bDMARDs which are not FDA-approved for the

treatment of JIA but are recommended in the ACR guidelines including anakinra,

rilonacept, rituximab, the TNF-α inhibitors as a class, and tocilizumab.

197 While the

TNF-α inhibitors have demonstrated excellent efficacy in the treatment of adult RA

as well as polyarticular JIA, they have not shown similar efficacy in the treatment of

systemic JIA. The exact pathophysiology of systemic JIA remains unclear, but the

pro-inflammatory cytokines IL-1 and IL-6 have been identified as targets of

pharmacotherapy.

197,217–219 Thus, IL-1 inhibitors anakinra, canakinumab, and

rilonacept as well as IL-6 inhibitor, tocilizumab, have demonstrated efficacy in the

treatment of systemic JIA, and their use is addressed in the ACR treatment

guidelines.

197

IL-1 inhibitors, anakinra and canakinumab, are recommended for the treatment of

systemic JIA, while rilonacept’s place in therapy remains unclear. Anakinra blocks

the action of IL-1α and IL-1β by inhibiting IL-1 binding to the interleukin-1 type

receptor (IL-1R1). While anakinra has shown suboptimal efficacy in the treatment of

adult RA, patients with systemic JIA have responded well to anakinra treatment.

Case reports of good response to anakinra in patients who were refractory to other

treatments for systemic JIA led to increased use of anakinra in patients with systemic

JIA.

217,217,220

In a small randomized, controlled trial in patients with systemic JIA, 8

out of 12 patients in the anakinra group achieved the primary outcome (30%

improvement in clinical status, resolution of fever, and 50% decrease or

normalization of both CRP and ESR) versus 1 out of 12 patients in the control group.

Furthermore, 10 of the patients in the control group were switched to anakinra after 1

month and nine of these patients also responded to anakinra treatment.

220 While

anakinra is not FDA-approved for JIA, the dose that has been used in clinical trials is

2 mg/kg subcutaneously daily, with a maximum daily dose of 100 mg.

220 As with all

of the bDMARDs, patients should be monitored for increased risk of infection when

taking anakinra. Anakinra would be an appropriate treatment for J.R. following lack

of response to NSAID and glucocorticoid monotherapies.

Canakinumab is a human monoclonal antibody, which binds IL-1β and blocks its

interaction with IL-1 receptors. It is FDA-approved for the treatment of systemic JIA

at a dose of 4 mg/kg subcutaneously every 4 weeks for patients with a body weight of

≥7.5 kg (maximum dose 300 mg).

221

In a randomized, placebo-controlled trial

evaluating canakinumab for the treatment of systemic JIA, 84% of subjects

experienced a 30% clinical response in the canakinumab group compared to only

10% in the placebo group (p < 0.001) 15 days after one dose of canakinumab.

222

In

another trial in patients receiving open-label canakinumab for 32 weeks, there was a

significantly lower risk of flares in the canakinumab patients and the average

glucocorticoid dose was reduced in the canakinumab group.

222 Canakinumab, like

other bDMARDs, has been associated with increased risk of infections. It has also

been associated with MAS. This association may be attributed to the severity of the

disease in patients treated with canakinumab and a causal relationship has not been

established.

222 Canakinumab would also be an appropriate treatment option for J.R.

The monthly dosing may be preferred over the daily dosing required with anakinra.

Rilonacept is an interleukin 1 inhibitor that binds IL-1β as well as IL-1α and IL-1

receptor antagonist with lesser affinity.

223 While rilonacept has demonstrated efficacy

for the treatment of systemic JIA, its place in therapy remains unclear.

224

It should not

be used as first-line therapy, and its use for continued disease activity was

considered uncertain according to the ACR guidelines.

197

Tocilizumab is a monoclonal antibody against the IL-6 receptor. It is

recommended for patients with systemic JIA with active systemic disease and

continued disease activity following a trial of glucocorticoid monotherapy,

csDMARD, or anakinra.

197

It is also recommended in systemic JIA patients without

systemic features who have an AJC > 0 following treatment with anakinra or a

csDMARD.

197 The TCZ dose used in clinic trials for systemic JIA is 8 mg/kg for

weight ≥30 kg or 12 mg/kg for weight <30 kg given intravenously every 2 weeks.

225

In a randomized trial of tocilizumab for systemic JIA, 71% of children who received

TCZ experienced a 70% improvement in clinic status, compared to 8%

p. 903

p. 904

of patients who received placebo.

227 Like canakinumab, there has been an

association between TCZ and MAS, while anakinra has been shown to be effective

in the treatment of MAS.

217

Patient J.R. has tried an NSAID and systemic glucocorticoid, but she continues to

have active systemic RA. Anakinra, canakinumab, and tocilizumab would all be

appropriate treatment options for J.R. Canakinumab is FDA-approved for systemic

JIA and has the most convenient dosing regimen of these three options. Therefore,

canakinumab would be the best option for J.R.

CASE 44-12

QUESTION 1: Seven-year-old C.E. has polyarthritis that consistently has not responded to NSAID or MTX

therapy. Given the many potential side effects, C.E.’s parents are concerned about her taking steroids and

refuse to let their daughter take them. They are worried about permanent joint damage and wish to try a

biologic agent in hopes of finally suppressing disease activity. They have heard that biologic drugs are “safer

than steroids” and want to know which agents are available to treat JIA in C.E.

There are three FDA-approved biologic agents available to treat JIA: etanercept,

adalimumab, and abatacept. As discussed in the previous section, canakinumab is

approved for the treatment of systemic JIA.

Etanercept is a recombinant TNF-receptor Fc fusion protein indicated for patients

2 years of age with polyarticular JIA. ETA is recommended for patients with

oligoarticular or polyarticular JIA, who continue to have active RA despite 3 months

of treatment with MTX at the maximum tolerated dosage.

199 The recommended dose

is 0.8 mg/kg (maximum 50 mg) subcutaneously weekly.

44 The safety of etanercept in

children is comparable to adults with the exception of significantly more abdominal

pain (17% of patients with JIA vs. 5% of adult patients with RA) and vomiting

(14.5% of patients with JIA vs. <3% of adult patients with RA). Patients with JIA

should be up-to-date on their immunizations before initiation of etanercept therapy

because the effect of etanercept on vaccine response is unknown. Safety and efficacy

data reflecting up to 10 years of treatment support the long-term use of etanercept for

JIA.

226

Adalimumab is a human monoclonal TNF-α antibody approved for use in patients

aged 2 years of age and older with moderately to severely active polyarticular JIA.

45

It is a weight-based dose (10 mg for patients 10 to <15 kg, 20 mg for patients 15 to

<30 kg, 40 mg for patients ≥30 kg) given as a subcutaneous injection every other

week.

45

In a study involving 171 patients on adalimumab monotherapy and in

combination with MTX, children taking combination therapy showed better disease

improvement than patients on adalimumab monotherapy.

45 Concomitant steroids,

salicylates, NSAIDs, or other analgesic agents may also be continued during

adalimumab use.

Abatacept is an injectable biologic agent that inhibits T-cell activation. This drug

received approval for JIA in 2008 and is indicated for use in patients 6 years and

older with moderate to severe active polyarticular juvenile idiopathic arthritis.

Patients weighing less than 75 kg receive a dose of 10 mg/kg via IV infusion for 30

minutes, while patients weighing 75 kg or more should receive the adult intravenous

regimen, with a maximum dose of 1,000 mg.

52 All patients receive doses at 2 and 4

weeks after the first infusion and then every 4 weeks thereafter.

52 Unlike TNF-α

agents, abatacept does not have an immediate onset and seems to exert its effect best

after repeated doses over the course of several months.

213

Other biologic agents, including the other TNF-α inhibitors, are not FDAapproved for JIA but have been studied. Available data from clinical trials suggest

that all of these treatments may be safe and effective for JIA with no evidence of

significant risk for serious adverse reactions. Owing to their mechanisms of action,

all biologic agents share the side effect of lowered infection resistance, and patients

must be monitored for signs of infection during treatment.

Of all FDA-approved bDMARDs, C.E. is a candidate for etanercept, adalimumab,

or abatacept therapy. Given that abatacept does not have an immediate onset,

etanercept or adalimumab may be preferred. Adalimumab with its biweekly dosing

schedule may be preferred compared to weekly dosing with etanercept. C.E. will

also be able to continue her concurrent NSAID and MTX therapies during

adalimumab treatment, because it is possible she will experience enhanced clinical

improvement on combination therapy versus adalimumab alone.

CASE 44-13

QUESTION 1: T.T. presents to rheumatology clinic on referral from her primary-care provider. She is 9 years

old and has been complaining at home of her shoes hurting her feet and not being able to run with her

classmates at school. On physical examination it is noted she has multiple swollen, erythematous joints

(tarsometatarsal and metatarsocuneiform joints bilaterally on the feet, ankles bilaterally, knees bilaterally). Her

CBC values are all normal, her ESR is normal, and her RF is positive. In addition to NSAID and steroid

therapy, the rheumatologist would like to start a DMARD agent. What DMARD options are available to treat

T.T.’s JIA?

Patients with both RF+ polyarthritis and early-onset JIA have poor prognosis in

terms of long-term joint function and should receive early consideration for DMARD

therapy. MTX is the DMARD of choice for polyarthritic JIA.

227 T.T. is showing

classic signs of RF+ polyarthritis and it would be appropriate to choose MTX as a

first-line agent for her therapy. The recommended dose of MTX for JIA treatment is

10 mg/m2 orally or subcutaneously each week. Food reduces the bioavailability of

MTX, so MTX should be administered on an empty stomach. Radiologic evidence of

improvement or slowing of joint damage has been demonstrated in patients with JIA

who responded to MTX therapy during a 2-year period.

228 Other DMARD options for

JIA include leflunomide, sulfasalazine, or hydroxychloroquine. MTX is favored over

these alternate csDMARDs and leflonomide is the preferred second-line

csDMARD.

199

CASE 44-13, QUESTION 2: What is the expected response to MTX treatment for T.T.?

The likelihood of long-term or permanent JIA-related joint damage is less than that

associated with adult RA; therefore, discontinuation of MTX should be attempted

when disease remission is apparent. The optimal time to discontinue MTX therapy

remains unknown; however, it probably should not be stopped sooner than 1 year

after disease remission, with slower withdrawal in patients at high risk for

relapse.

229,230Young age at diagnosis (<4.5 years) and oligoarthritis that progresses to

polyarthritis seem to be the greatest risk factors for relapse.

229,231

Children tolerate MTX therapy well and generally experience few serious or

troublesome adverse effects (e.g., transient liver enzyme elevations, nausea,

vomiting, and oral ulcerations).

230 These adverse effects are reduced with daily folic

acid therapy (1 mg) or weekly folinic acid (the day after MTX dosing). Liver toxicity

monitoring in JIA is the same as the guidelines recommend for MTX therapy in adult

RA, including biopsy recommendations. The combination therapy of MTX and other

DMARDs has not been fully evaluated in pediatric patients.

p. 904

p. 905

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

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League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–2581. (14)

Beukelman T et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile

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Ringold S et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of

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arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum.

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Singh JA et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

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Smolen JS et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and

biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492–509. (26)

Key Websites

The American College of Rheumatology. Rheumatology image bank. http://images.rheumatology.org/.

Accessed March 30, 2016.

Arthritis Foundation. What is arthritis? http://www.arthritis.org/about-arthritis/understanding-arthritis/.

Accessed July 25, 2015. (1)

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