The knowledge base of the pathogenesis, classification, diagnosis, outcome assessment, and management of pediatric rheumatic diseases has grown tremendously in the past few years. Notable progress has been made in understanding the chronic forms of juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), dermatomyositis, vasculitis, and hereditary febrile syndromes. In addition, continued rigorous clinical trials and translational studies probably will improve understanding of these disorders in the near future.
In this article, we review important recent developments in pediatric rheumatology. We also highlight the features that help distinguish between pediatric rheumatic diseases and their analogues in adult rheumatology.
JUVENILE IDIOPATHIC ARTHRITIS
This umbrella term refers to a group of disorders that are characterized by chronic arthritis. JIA is defined as persistent arthritis of 1 or more joints for at least 6 consecutive weeks in a child younger than 16 years; other identifiable causes of arthritis are excluded. JIA is the most common chronic rheumatic condition in children.
Newer classifications. Now 3 classification systems are used for JIA (Table). Each system attempts to identify clinically homogeneous subtypes to facilitate communication about epidemiology, therapeutics, and outcomes among physicians globally.
The newer classifications, issued by the European League Against Rheumatism (EULAR) and by the International League of Associations for Rheumatology (ILAR), include psoriatic and enthesitis-related arthritis (spondyloarthropathy). The ILAR classification also takes into account the course of disease after 6 months (ie, "extended oligoarticular" refers to an oligoarticular onset with a polyarticular course).1 In the latter classification, rheumatoid factor-positive polyarticular JIA probably represents the early expression of adult seropositive rheumatoid arthritis (RA) with the same human leukocyte antigen associations, extra-articular manifestations, and poor prognosis.
It is important to remember that JIA is not just RA in little adults. In children with JIA, unique developmental, growth, and nutritional considerations are involved. Delayed puberty and nutritional abnormalities are common. Increased resting energy expenditure is found, especially in patients with systemic-onset JIA (SoJIA), which has important nutritional implications (eg, children with SoJIA have increased caloric and iron requirements2). The causes of generalized growth delay are multifactorial. Localized growth retardation or accelerated maturation of bone can lead to micrognathia and limb-length discrepancies (Figure 1).
Psychological and eye difficulties seen. Studies have shown that children with JIA often experience psychological difficulties in addition to physical disability. Depression occurs in about 5% of patients with JIA; anxiety, correlated with increased frequency and intensity of pain and fatigue, is seen in about 10% of patients.3 Patients with prepubertal JIA engage in significantly less physical activity and significantly more sleep than healthy controls. Cognitive behavioral pain management has been shown to be effective in patients with JIA.4
Children with JIA also may experience eye problems.5,6 Chronic iritis is a somewhat common complication in some forms of JIA. Children aged 6 years or younger with oligoarticular or polyarticular JIA and a positive antinuclear antibody (ANA) test result are at very high risk for uveitis. Initially, they should undergo an ophthalmological examination every 3 to 4 months. In addition, children with juvenile psoriatic arthritis should have a slit-lamp examination every 6 months (asymptomatic uveitis occurs in up to 17% of patients).
Children aged 7 and older or those who have a negative ANA test result have a moderate risk of uveitis and need an eye examination every 6 months. Because there is little or no risk of uveitis with SoJIA, an eye examination may be done only every 12 months. The risk of uveitis decreases after 4 years and then again after 7 years; ophthalmological surveillance is less frequent after these milestones.
Life-threatening complication. Macrophage activation syndrome (MAS) is a life-threatening complication of systemic JIA and SLE; in a few cases, it may occur in healthy children after viral infection. MAS presents with an acute onset of fever, pancytopenia, liver dysfunction, hepatosplenomegaly, coagulopathy, neurological symptoms, hypertriglyceridemia, hyperferritinemia, and a decreasing erythrocyte sedimentation rate (ESR). In systemic JIA, MAS may be triggered by infection (especially Epstein-Barr virus infection) or by a change in disease activity or therapy. The pathogenesis of MAS appears to be related to impaired cytotoxic activity of natural killer and CD8 lymphocytes.7
It can be difficult to distinguish between a systemic JIA flare and MAS. The clinical criteria most useful for identifying MAS are CNS involvement; hemorrhage; and laboratory results that show pancytopenia, decreasing ESR, high ferritin level, and coagulopathy.8 The gold standard of diagnosis is demonstration of hemophagocytosis in bone marrow or other affected tissue, such as in the liver.
Treatment of patients with MAS includes high-dose corticosteroids and, if the response is not satisfactory, the addition of cyclosporin A. Treatment with etoposide and dexamethasone may be indicated.
JIA treatment differences. Treatment of patients with JIA involves significant differences from those with RA . NSAIDs may be used initially in patients with JIA (only naproxen, tolmetin, ibuprofen, diclo- fenac, and meloxicam are approved for use in children). The choice of NSAID may be based on the taste of the medication and the convenience of the dosing regimen. Children are less likely than adults to have serious GI complications, but NSAID-induced pseudoporphyria is a known complication in children, especially with naproxen in young children who have fair skin.
Patients who have oligoarticular JIA or polyarticular JIA with a few very active joints may be treated with intra-articular corticosteroid injections. These have been shown to not only decrease the synovitis but also to prevent growth disturbances.
Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) in pediatric rheumatology. GI toxicity is the most common adverse event (about 13% of patients)9; hepatotoxicity and pulmonary disease are very rare in children. Children should be encouraged to take a daily multivitamin with folic acid.
Advise adolescents who are treated with MTX to avoid alcohol intake (a known risk factor for hepatotoxicity) and pregnancy (MTX is teratogenic). Patients should be advised to stop taking MTX 3 to 6 months before attempting to conceive. Reassure patients that female fertility is not affected by MTX and that male sterility induced by MTX is reversible.
Sulfasalazine probably will be more effective in oligoarticular JIA, juvenile ankylosing spondylitis, and psoriatic arthritis than in other conditions. This agent should be avoided in SoJIA because of its reported association with MAS.
More aggressive treatment. Aggressive treatment with immunomodulatory therapies is becoming more commonplace, even in the pediatric patient population. Tumor necrosis factor a (TNF-a) appears to be the predominant proinflammatory cytokine in pauciarticular and polyarticular JIA. Controlled trials showed very good efficacy and safety with etanercept after 4 years of treatment.10 Etanercept is the only TNF-a inhibitor that is FDA-approved for children with JIA for whom MTX was not successful. A purified protein derivative test should be performed in all children before any anti-TNF-a drug is started to evaluate them for tuberculosis infection.
In a randomized placebo-controlled trial of patients with JIA, infliximab at 3 mg/kg/d did not meet the primary end point at 14 weeks; however, at 6 mg/kg/d, it resulted in clinically important improvement. Infliximab was well tolerated by both groups of patients, but the 3 mg/kg/d dosage was associated with higher immunogenicity.
Many biological agents other than etanercept and infliximab currently are in clinical trials for JIA. These include an interleukin (IL)-1 receptor antagonist (anakinra), a more humanized anti-TNF-a antibody (adalimumab), a modulator of T cell activation (abatacept), and an anti-IL-6 receptor antibody (tocilizumab).
1. Petty RE, Southwood TR, Manners P, et al; International League of Associations for Rheumatology. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis; second revision, Edmonton, 2001. J Rheumatol. 2004;31:390-392.
2. Milojevic DS, Ilowite NT. Treatment of rheumatic diseases in children: special considerations. Rheum Dis Clin North Am. 2002;28:461-482.
3. Schanberg LE, Anthony KK, Gil KM, Maurin EC. Daily pain and symptoms in children with polyarticular arthritis. Arthritis Rheum. 2003;48: 1390-1397.
4. Walco GA, Varni JW, Ilowite NT. Cognitive-behavioral pain management in children with juvenile rheumatoid arthritis. Pediatrics. 1992;89:1075-1079.
5. Weiss JE, Ilowite NT. Juvenile idiopathic arthritis. Pediatr Clin North Am. 2005;52:413-442.
6. Yancey C, White P. Guidelines for ophthalmologic evaluations in children with juvenile rheumatoid arthritis. Pediatrics. 1993;92:295-296.
7. Grom AA, Villanueva J, Lee S, et al. Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome. Pediatrics. 2003;142:292-296.
8. Ravelli A, Magni-Manzoni S, Pistorio A, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr. 2005;146;598-604.
9. Ilowite NT. Current treatment of juvenile rheumatoid arthritis. Pediatrics. 2002;109:109-115.
10. Lovell DJ, Reiff A, Jones OY, et al. Long-term safety and efficacy of etanercept in children with polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 2006;54:1987-1994.
11. DeWitt E, Sherry DD, Cron RQ. Pediatric rheumatology for the adult rheumatologist, I: therapy and dosing for pediatric rheumatic disorders. J Clin Rheumatol. 2005;11:21-33.
12. Cameron JS. Lupus nephritis in childhood and adolescence. Pediatr Nephrol. 1994;8:230-249.
13. Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005; 353:2219-2228.
14. Klein-Gitelman MS, Waters T, Pachman LM. The economic impact of intermittent high-dose intravenous versus oral corticosteroid treatment of juvenile dermatomyositis. Arthritis Care Res. 2000; 13:360-368.
15. Bowyer SL, Blane CE, Sullivan DB, Cassidy JT. Childhood dermatomyositis: factors predicting functional outcome and development of dystrophic calcification. J Pediatr. 1983;103:882-888.
16. Roifman CM. Use of intravenous immune globulin in the therapy of children with rheumatological diseases. J Clin Immunol. 1995;15(6 suppl):42S-51S.
17. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110:2747-2771.
18. Fukushige J, Takahashi N, Ueda Y, Ueda K. Incidence and clinical features of incomplete Kawasaki disease. Acta Paediatr. 1994;83:1057-1060.
19. Sundel RP, Baker AL, Fulton DR, Newburger JW. Corticosteroids in the initial treatment of Kawasaki disease: report of a randomized trial. J Pediatr. 2003; 142:611-616.
20. Simon A, van der Meer JW. Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes. Am J Physiol Regul Integr Comp Physiol. 2007;292:R86-R98.
21. Goldbach-Mansky R, Dailey NJ, Canna SW, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355:581-592.
22. Stojanov S, Kastner DL. Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr Opin Rheumatol. 2005;17:586-599.