Update on Pediatric Rheumatology

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).

Vaccination issues. Issues of vaccination are important to consider for children who have JIA. If possible, age-appropriate immunization schedules should be completed before the start of immunosuppressive therapy, including MTX and etanercept.¹¹ Children who are taking more than 2 mg/kg/d of corticosteroids or more than 20 mg for more than 14 days are considered at high risk; they should not be immunized with live virus vaccines until 1 month after cortico-steroids have been discontinued, according to the American Academy of Pediatrics Red Book recommendations. Live virus vaccines should be withheld for at least 3 months after immunosuppressive chemotherapy. In the case of anti-TNF-a therapy, a minimum of a 3-month interval between live vaccine administration (particularly varicella) and the start of therapy is recommended.⁹

Annual inactivated influenza vaccination is recommended for immunocompromised children older than 6 months. The heptavalent pneumococcal conjugate vaccine (PCV7) is administered routinely to all children older than 24 months. Immunocompromised and asplenic (anatomic or functional) children (including those with SLE) should receive the 23- valent pneumococcal polysaccharide vaccine (PPV23) after age 2 years (more than 2 months after their last PCV7); there should be 1 revaccination 3 to 5 years later if the child is younger than 10 years, or 5 years later if the child is older than 10 years. Household contacts and health care professionals who are caring for immunocompromised children should receive inactivated influenza vaccine, but not the live intranasal preparation, once a year.

SYSTEMIC LUPUS ERYTHEMATOSUS

SLE is a multisystem, chronic, but often episodic autoimmune disease characterized by the presence of antibodies to nuclear antigens. The diagnosis of SLE is made in about 20% of patients during their childhood; in most pediatric patients with SLE, the diagnosis is made during their adolescence. Before puberty, the female-to-male ratio is 3:1; after puberty, the ratio becomes 9:1.

Renal involvement with SLE is more common and more severe in children than in adults. Lupus nephritis occurs in about 75% of children.¹² Children with SLE are at high risk for atherosclerosis, probably because of the longer duration of childhood-onset SLE. If management of dyslipoproteinemia with improved diet, exercise, and fish oil caplets does not result in improvement, some children might require treatment with statins.

Children treated like adults. Treatment of children with SLE is similar to treatment of adults with SLE. Children seem to respond to therapy better, although they have more severe disease than adults. Children also tolerate most medications (except corticosteroids) better because they are less likely to have other comorbid conditions and they have greater regenerative capacity. Because retinal toxicity may occur in children who are taking hydroxychloroquine, they should have a routine ophthalmological examination every 6 months and visual field testing every year.

Corticosteroids are associated with multiple adverse effects in children; therefore, doses are reduced as quickly as clinical improvement allows. Corticosteroids are potent inducers of osteopenia in children and a major cause of stunted growth. They also may cause skin striae, which might be a source of cosmetic concern, especially for adolescent girls. Toxicity-sparing strategies include use of alternate-day or intravenous "pulse" dosing of methylprednisolone.

Roles of immunosuppressive therapy. Immunosuppressive drugs play 2 important roles in SLE: corticosteroid-sparing agents and corticosteroid-resistant disease managers. Cyclophosphamide (CYC) is the drug of choice for proliferative glomerulonephritis and for CNS disease; pulse CYC treatment is less toxic. CYC-induced testicular and ovarian failure is least frequent in prepubertal children and increases with maturation of the gonads. After puberty, the option of sperm banking should be a part of informed consent procedure.

In our experience, the use of ice caps for girls seems to decrease the incidence of CYC-induced alopecia. In a recent 24-week trial, mycophenolate mofetil was as effective as intravenous CYC in inducing remission of lupus nephritis and had a more favorable safety profile in adults.¹³ Mycophenolate mofetil is being used with increasing frequency.

NEONATAL LUPUS ERYTHEMATOSUS

NLE, which may occur in infants whose mothers have SLE, is caused by transplacental transfer of maternal antibodies. Almost all mothers of the affected infants are anti-Ro or anti-La antibody-positive. The most common manifestations of NLE are hematologic, cutaneous, hepatic, and cardiac abnormalities.

Most NLE manifestations resolve without sequelae after an average of 6 months, coinciding with the disappearance of maternal antibodies. However, congenital heart block is permanent; if it is detected early in pregnancy, placement of a permanent pacemaker may be necessary. Mortality is still very significant. Cross-placental transfer of maternal autoantibodies is responsible for the vast majority of cases of "idiopathic" congenital heart block.

Rash and, occasionally, thrombocytopenia occur in NLE. Antibody-mediated congenital heart block may occur in neonates born to mothers with the antibodies but without SLE.

JUVENILE DERMATOMYOSITIS

JDM, a serious illness with significant morbidity and mortality, is different from its adult analogue. Polymyositis is much less common in children than it is in adults. Vasculopathy and vasculitis are much more prominent features. The devastating complication of calcinosis-a dystrophic calcification of inflamed or damaged muscle and nearby tissue that occurs in areas of trauma or pressure points-is much more common in children than it is in adults. Treatment is directed toward preventing ongoing myositis, protecting involved areas from trauma, and managing infection promptly.

Corticosteroids are the mainstay of treatment for children with JDM. The trend is to initiate treatment with weekly intravenous high-dose (pulse) methylprednisolone.¹⁴ Unlike in adults with polymyositis/dermatomyositis, there is no significant increased risk of an associated underlying malignancy in children with JDM. Fewer than 10% of children have associated myositis-specific antibodies. If a patient has the characteristic rash, symmetric proximal muscle weakness, and elevated serum muscle enzyme levels, demonstrating an abnormal electromyogram or muscle histology result is not needed to make the diagnosis.

Best treatment. The best treatment outcome for children with JDM was shown with an initial dosage of 2 mg/kg/d of corticosteroids for at least 2 months (2-year total duration of anti-inflammatory treatment, with adequate assessment of response to therapy).¹⁵ MTX may be used for its corticosteroid-sparing effect, and to treat unresponsive severe rash or mucositis, progressive or disabling muscle weakness, treatment-resistant cardiac or pulmonary complications, recurrent GI crises, and life-threatening impairment of swallowing or airway function.

Intravenous immunoglobulin (IVIg) proved to be beneficial in improving muscle strength and skin manifestations.¹⁶ For recalcitrant and severe disease, monthly intravenous CYC may be used. TNF-a appears to be a pivotal cytokine in JDM and an attractive target for therapy.

KAWASAKI DISEASE

Formerly called mucocutaneous lymph node syndrome, KD is one of the most common vasculitides of childhood. The incidence appears to be highest in infants and toddlers younger than 3 years. KD is characterized by systemic inflammation manifested by fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, rash, extremity changes, and lymphadenopathy (Figure 2). These clinical signs form the basis for the diagnostic criteria for KD.

Children in whom KD is suspected but who do not fulfill diagnostic criteria may have "incomplete" or atypical KD: they manifest the typical clinical features of KD but simply lack sufficient criteria to warrant the diagnosis of KD.¹⁷ In a retrospective report of 242 Japanese children with KD, 10% had a diagnosis of incomplete KD.¹⁸

KD typically is a self-limited condition and lasts for an average of 12 days without therapy. The major complication of KD, coronary artery aneurysm, is most likely to occur in boys of Asian ancestry younger than 1 year. Obtain an echocardiogram early in the acute phase of illness and 6 to 8 weeks after disease onset.

IVIg and aspirin. Ideally, a single dose of IVIg (2 g/kg) should be administered within the first 10 days of illness or, if there is continuing evidence of inflammation, as soon as possible after the diagnosis is made. If the fever does not resolve within 48 hours, about one fourth of patients require a second dose of IVIg.

High-dose aspirin (80 to 100 mg/kg/d) also is used; it is decreased to 3 to 5 mg/kg/d 48 hours after the resolution of fever. Aspirin is continued until markers for acute inflammation (platelet count and ESR) return to normal, unless coronary artery abnormalities are detected by echocardiography. Patients with recalcitrant disease may be re-treated with IVIg and, if they are still unresponsive, high doses of corticosteroids.¹⁹

PERIODIC FEVER SYNDROMES

Familial periodic fever syndromes, otherwise known as hereditary autoinflammatory syndromes, are a group of Mendelian disorders characterized by recurrent unprovoked episodes of fever and localized inflammation. The general hypothesis is that these syndromes represent inborn errors in the regulation of the innate immune response. Most of these syndromes are caused by increased activation of pattern recognition molecules of the innate immune system. Both exogenous and endogenous molecules may serve as triggers.

Specific characteristics. At least 8 major clinical syndromes have specific characteristics.²⁰ The fever attacks often start in childhood but may begin in adolescence, as in familial Mediterranean fever (FMF), or in adulthood, as in TNF-receptor-associated periodic syndrome (TRAPS). Disease duration ranges from 1 day (familial cold autoinflammatory syndrome) to weeks (TRAPS).

Symptoms of periodic fever syndromes caused by inflammation accompany the fever: serositis, myalgia, arthralgia or arthritis, and erythematous skin lesions. The symptoms resolve spontaneously, and there is complete remission between episodes, except in chronic infantile neurological cutaneous and articular (CINCA) syndrome, also known as neonatal onset multisystemic inflammatory disease (NOMID).

The proinflammatory cytokine IL-1b plays an important role in the pathophysiology of these syndromes. IL-1b initially is secreted as an inactive precursor, pro-IL-1b. The cleavage (and activation) of pro-IL-1b is performed by caspase 1, a component of an inflammasome (a cytosolic, multiprotein complex that consists of NOD-LRR protein as a sensing protein, 1 or more adaptor proteins, and 1 or more inflammatory caspases as effector proteins).

In autoinflammatory syndromes, such as cryopyrin-associated periodic syndrome and FMF, defective protein components of an inflammasome (cryopyrin and pyrin, respectively) cause an exaggerated downstream response in which caspase 1 activation leads to conversion of pro-IL-1b to bioactive IL-1b. This hypothesis is sustained by the good response to treatment with IL-1 receptor antagonist medication (anakinra).²¹ The pathogenesis of some other autoinflammatory syndromes (hyper-IgD syndrome and TRAPS) is much less clear but also seems to involve the proinflammatory cytokines IL-1b and TNF-a.

Fever treatment. In FMF, treatment with daily oral colchicine may reduce the frequency and severity of the attacks and usually prevents amyloidosis. Patients with TRAPS generally do not respond to colchicine, but they are responsive to high-dose corticosteroids. Clinical and laboratory inflammation in TRAPS also may be improved with etanercept.²² Anakinra may induce remission in Muckle-Wells syndrome and resolution of uveitis, rash, and fever in patients who have NOMID/CINCA syndrome.

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