Challenges in the Diagnosis and Management of Systemic Juvenile Idiopathic Arthritis

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Challenges in the Diagnosis and Management of Systemic Juvenile Idiopathic

Arthritis

Raphael Hirsch, MD University of Pittsburgh School of Medicine

http://www.medscape.com/viewarticle/567668

Introduction

The recent American College of Rheumatology (ACR) 71st Annual Meeting, held

in Boston, Massachusetts, included a comprehensive, 60-minute

State-of-the-Art Symposium on systemic juvenile idiopathic arthritis (SJIA).

Although it is the rarest form of juvenile arthritis, SJIA is the most

difficult to treat and is often associated with the worst outcome.

The presentation was led by M. Laxer, MD, at The Hospital for Sick

Children, Toronto, Ontario, Canada, and began with a review of how to

distinguish SJIA from other forms of juvenile arthritis and febrile

syndromes of childhood. This was followed by a discussion of the important

complications of SJIA. The session concluded with a discussion of the use of

new therapies in the treatment of SJIA. The symposium was moderated by

Suzanne L. Bowyer, MD, at the Whitcomb Riley Hospital, Indianapolis,

Indiana.

Diagnosis of SJIA

The diagnosis of SJIA, according to the classification criteria,[1] requires

arthritis in at least 1 joint, daily fever for at least 2 weeks, and at

least one of the following: evanescent erythematous rash, generalized lymph

node enlargement, hepatomegaly and/or splenomegaly, or serositis.

Clinical and Laboratory Features of SJIA

Arthritis usually develops within the first 3 months, but it can be absent

during the early stages of the disease, making the diagnosis difficult.

About half of patients can go into spontaneous remission, but half develop

chronic, persistent disease. The hips and wrists are frequent sites of

destructive arthritis.

Unusual features of SJIA include myocarditis, pneumonia, pulmonary

hypertension, aseptic meningitis, nephritis, uveitis, and vasculitis.

Typical laboratory features of SJIA include microscopic anemia, neutrophilic

leukocytosis, thrombocytosis, elevated C-reactive protein (CRP) and

erythrocyte sedimentation rate (ESR), hypoalbuminemia, elevated serum

ferritin, and hypergammaglobulinemia.

Differential Diagnosis

The differential diagnosis of SJIA can be challenging and includes fever of

unknown origin, such as malignancy, infection, other autoimmune disease,

Kawasaki disease, and other inflammatory disorders.

Although SJIA is classified as an autoimmune disease, many of its features,

as well as its response to treatment -- particularly with anti-interleukin

(IL)-1 agents (discussed below) -- more closely resemble the

autoinflammatory disorders, also referred to as hereditary periodic fever

syndromes. These include familial Mediterranean fever, tumor necrosis factor

(TNF) receptor-associated periodic fever, hyperIgD and periodic fever, and

cryopyrin-associated periodic syndrome.

Complications of SJIA

Joint Damage and Disability

Between 30% and 45% of patients with SJIA develop radiographic evidence of

joint damage within 2 years of disease onset. Between 22% and 42% of

patients develop moderate-to-severe disability. Laxer, MD, presented

data from a recent study suggesting that poor outcome was more likely in

patients with a persistent, as opposed to a monocyclic, disease course.[2]

Other studies have suggested that predictors of severe arthritis at 6 months

include persistent need for steroids, polyarthritis, and elevated white

blood cell and platelet counts.[3-6] De Benedetti and colleagues[7] have

suggested that patients with elevated serum levels of migration inhibitory

factor have a longer duration of steroid use, more active joints, fewer

remissions, and higher disability scores.

Poor Growth and Osteoporosis

Almost half of patients with SJIA are more than 2 standard deviations below

their target heights. This may have multiple causes, including the disease

itself as well as the prolonged use of prednisone. There is a strong

positive correlation between poor growth and duration of prednisone therapy.

The use of growth hormone may be of benefit in these children. In a recent

study of 30 patients who were randomized to receive growth hormone for 3

years, improved height velocity and height were observed despite no

difference in inflammation of prednisone dose.[8] However, bone health did

not improve. Patients with SJIA are at risk for osteoporosis and fracture,

most commonly vertebral. Contributing factors likely include disease

activity, poor nutrition, reduced physical activity, delayed puberty, and

prednisone treatment.

Macrophage Activation Syndrome

Macrophage activation syndrome (MAS) is one of the most serious potential

complications of SJIA and is a significant cause of mortality. It effects 7%

to 10% of patients and appears to be a consequence of uncontrolled release

of cytokines from activated T cells and macrophages. Early recognition of

MAS is essential because the mortality rate, if untreated, is 8% to 22%. MAS

resembles hemophagocytic lymphohistiocytosis. It can be difficult to

differentiate between MAS and SJIA flare. Helpful clinical features that

should lead to a suspicion of MAS include a persistent (rather than

quotidian) fever, a petechial or purpuric (rather than evanescent) rash, the

absence of arthritis and serositis, and the presence of encephalopathy.

Laboratory features include falling white blood cell, hemoglobin, and

platelet counts; a falling or normal ESR with elevated CRP; elevated liver

enzymes; evidence of coagulopathy; and marked elevation of serum ferritin.

Elevated soluble CD25 and CD163 may also be markers of MAS,[9] although

these are not routinely available. The triggers for MAS are not clear, but

have been reported to include infection, certain medications, and autologous

stem cell transplant. Ravelli and colleagues[10] have proposed preliminary

diagnostic criteria for MAS. It is essential to initiate treatment quickly

with high-dose steroids and cyclosporine A.

Therapy for SJIA

SJIA is less responsive to conventional drug therapies, including

methotrexate, than the other forms of juvenile arthritis. The response to

anti-TNF treatment has also been disappointing. However, just in the past

few years, novel biologic agents have been tested that appear very

promising.

Anti-IL-1

IL-1-beta induces several of the features of SJIA and is elevated in

patients' sera during fever spikes. The IL-1 receptor antagonist anakinra is

effective for the treatment of autoinflammatory disorders. In a recent case

series, the IL-1 receptor antagonist anakinra* induced complete remission in

7 of 9 children with a very rapid response, usually within 2 weeks.[11]

Response was somewhat less dramatic in a second case series with a response

rate of 50% and a better response for the systemic features than for the

arthritis. Adverse effects were mild and commonly included pain at the site

of injection.

Anti-IL-6

There is substantial evidence that IL-6 is a major mediator of SJIA.

Increased serum levels of IL-6 are associated with the fever and severity of

arthritis. IL-6 is a major inducer of CRP, reduces iron levels, and

increases ferritin. Because of evidence implicating IL-6 in SJIA, the

anti-IL-6 antibody tocilizumab* is being investigated. In a preliminary

open-label study of 11 children in Japan with severe SJIA refractory to

high-dose steroids, 10 patients had rapid and dramatic improvement within 2

weeks, with resolution of fever and normalization of CRP.[12] During the 40-

to 80-day follow-up period, all patients achieved an ACR70, indicating at

least a 70% improvement. Long-term observation over 4 years in 4 children

showed sustained improvement.[13] Three of the 4 children were able to be

weaned off steroids within 12 weeks, and steep growth was observed. Adverse

effects were mild and included transient elevation of liver enzymes, upper

respiratory infections, and skin infections. A controlled study is currently

under way.

Thalidomide

Encouraging results have been reported with thalidomide*.[14] In 13 patients

with SJIA, 11 reached a 50% response rate with reduction in prednisone dose.

Side effects included sedation, constipation, and short-lived parasthesiae.

Autologous Stem Cell Transplant

A recent trial reporting the use of stem cell transplant in 18 patients with

unresponsive SJIA had a high morbidity and mortality rate.[15] Two patients

died of early MAS. Five patients failed the treatment with disease

progression. Five patients relapsed, 4 within the first year. However, 6

patients achieved remission and 5 achieved a partial response.

Conclusions

This State-of-the-Art Symposium on SJIA held at the 2007 ACR meeting

provided a valuable update on this challenging disorder. SJIA is unique from

other forms of juvenile arthritis because it behaves more like an

autoinflammatory disease than an autoimmune disease. The ability to predict

poor outcomes before irreversible damage allows for earlier therapeutic

intervention. New therapies may allow for improved outcomes.

*Anakinra and thalidomide have been used off-label. Tocilizumab has not been

US Food and Drug Administration (FDA)-approved for SJIA.

This activity is supported by an independent educational grant from

Bristol-Myers Squibb.